Review Article New Perspectives on How to Discover Drugs ...

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2013 Article ID 627375 25 pageshttpdxdoiorg1011552013627375

Review ArticleNew Perspectives on How to Discover Drugs fromHerbal Medicines CAMrsquos Outstanding Contribution toModern Therapeutics

Si-Yuan Pan1 Shu-Feng Zhou2 Si-Hua Gao3 Zhi-Ling Yu4

Shuo-Feng Zhang1 Min-Ke Tang1 Jian-Ning Sun1 Dik-Lung Ma5

Yi-Fan Han6 Wang-Fun Fong4 and Kam-Ming Ko7

1 School of Chinese Medicine Beijing University of Chinese Medicine Beijing 100102 China2 College of Pharmacy University of South Florida Tampa FL 33612 USA3 School of basic medicine Beijing University of Chinese Medicine Beijing 100102 China4 School of Chinese Medicine Hong Kong Baptist University Hong Kong5 Department of Chemistry Hong Kong Baptist University Hong Kong6Department of Applied Biology amp Chemical Technology Hong Kong Polytechnic University Hong Kong7Division of Life Science Hong Kong University of Science amp Technology Hong Kong

Correspondence should be addressed to Si-Yuan Pan siyuan-pan163com

Received 16 September 2012 Accepted 29 January 2013

Academic Editor Hyunsu Bae

Copyright copy 2013 Si-Yuan Pan et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

With tens of thousands of plant species on earth we are endowed with an enormous wealth of medicinal remedies from MotherNature Natural products and their derivatives represent more than 50 of all the drugs in modern therapeutics Because of the lowsuccess rate and huge capital investment need the research and development of conventional drugs are very costly and difficultOver the past few decades researchers have focused on drug discovery from herbal medicines or botanical sources an importantgroup of complementary and alternative medicine (CAM) therapyWith a long history of herbal usage for the clinical managementof a variety of diseases in indigenous cultures the success rate of developing a new drug from herbal medicinal preparations shouldin theory be higher than that from chemical synthesisWhile the endeavor for drug discovery from herbal medicines is ldquoexperiencedrivenrdquo the search for a therapeutically useful synthetic drug like ldquolooking for a needle in a haystackrdquo is a daunting task Inthis paper we first illustrated various approaches of drug discovery from herbal medicines Typical examples of successful drugdiscovery from botanical sources were given In addition problems in drug discovery from herbal medicines were described andpossible solutions were proposed The prospect of drug discovery from herbal medicines in the postgenomic era was made withthe provision of future directions in this area of drug development

1 Introduction

Thepharmaceutical industry is one of the pillar industries foreconomic development worldwide In 2006 global spendingon prescription drugs topped US$ 643 billion and the USAaccounted for almost half of the global pharmaceuticalmarket with US$ 289 billion in annual sales [1] Nowadayshumans cannot live well without medicine particularly inthe developed countries Although drug discovery has beendriven by a variety of technology platforms (Figure 1) which

can also expedite the development of therapeutic agentsfrom herbal medicines drug development remains a lengthyprocesswith a low rate of success and huge capital investmentOn average it takes about 10ndash15 years for a newly synthesizedcompound to become a marketable therapeutic agent andthe cost in 2006 was approximately C 1 billion [2] In 2005Big Pharma spent about US$ 50 billion which is more thandouble the amount spent in 1996 However in that year only22 new drugs were approved by the Food and Drug Admin-istration (FDA) in USA whereas 53 new drugs reached the

2 Evidence-Based Complementary and Alternative Medicine

Drug discovery

Automated separation techniques

Metabonomics

Bioinformatics

Proteomics

Biochip Genomics

System biologyTranscriptomics

Transgenic and RNAi technology

Computer-aideddrug design

High-throughput andhigh content screening

Figure 1 An array of technology platforms driving drug discovery

market in 1996 [3 4] Despite the protracted time courseof development only one or two in ten thousand of suchchemical compounds have proven to be clinically efficaciousand safe for approval by regulatory agencies In fact abouthalf of all drug candidates fail in the late stages of clinicaltrials Furthermore soon after their approval some newdrugs have to be withdrawn from the market due to severeside effects and clinical risks that are not detected in Phase IIItrials For example Vioxx (rofecoxib) which was launched in1999 was withdrawn in 2004 due to an increased risk of heartattack in users As a result the drug only existed in themarketfor 5 years and this was compounded by the huge sum (US$485 billion) of compensation involved in lawsuits [5] Giventhat the development of synthetic chemicals for therapeuticuse is by and large a random process that might result inserendipitous discoverymany pharmaceutical companies arenow focused on the development of plant-derived drugs

Complementary and alternative medicine therapies(CAMTs) which have been gaining popularity throughoutthe world are classified into drug-based CAMT and non-drug-based CAMT [6] Among various drug-based CAMTsmedicines (more than 80) commonly practiced are herbsof plant origin Human beings have evolved from the simpleherbivorous animals to omnivorous ones As such we noweat both plants and meats A wealth of experience on theapplication of herbalplant materials used in promotinghealth has accumulated over centuries and the informationis readily available for modern scientific research on drugdiscovery The earliest evidence of human use of plants forhealing can date back to the Neanderthal period [7] As aconsequence plant-derived herbs may interact favorablywith the human body and hence produce beneficial effectsin terms of health promotion Interestingly it has beenobserved that nonhuman vertebrates will eat some typesof plants for self-medication under disease conditions[8ndash10] Not surprisingly the observations of eating behaviorand serendipitous events in wild animals have led to thediscovery of herbsplants with therapeutic potential Inthis regard the study on self-medication in animals mayoffer a novel approach to drug discovery for humans For

instance novel antimalarial compounds were isolated fromthe leaves of Trichilia rubescens based on a behavioral surveyof chimpanzees from a natural population in Uganda [2]

In two recent articles we have discussed a total of tenapproaches in new drug discovery as well as the researchand development of traditional herbal medicine ldquo(THM)rdquo inrelation to modern drug discovery [11 12] While advancesin new technologies have revolutionized the process of drugdiscovery the successful development of a novel therapeuticagent is critically dependent on whether the process paysrespect to nature adopts new approachesconcepts andinvolves the studies on ADMET (ie absorption distribu-tion metabolism excretion and toxicity) in the early stagesof drug discovery Furthermore the safe and optimal useof herbal medicines requires a full understanding of theirADME and herb-syntheticherb-herb interaction profiles[13ndash16] In this paper we focused on the discovery of chem-icals for therapeutic usage from herbal medicines especiallyTHMwith an extremely valuable rich lengthy and extensivepractical history

2 Current Approaches of Drug Discovery fromHerbal Medicine

Today approximately 80 of antimicrobial cardiovascularimmunosuppressive and anticancer drugs are of plant origintheir sales exceeded US$ 65 billion in 2003 [17] It is widelyaccepted that more than 80 of drug substances are eitherdirectly derived from natural products or developed froma natural compound [18] And in fact around 50 ofpharmaceuticals are derived from compounds first identifiedor isolated from herbsplants including organisms animalsand insects as active ingredients [19] Drug discovery fromherbsmay be divided into three stages namely predrug stagequasidrug stage and full-drug stage They are described indetail in Figure 2

21 Predrug Stage It has been estimated that approximately420000 plant species exist on earth but for most of these

Evidence-Based Complementary and Alternative Medicine 3

only very limited knowledge is available Three approacheswhich are closely related to diet (foodstuffs) medical practice(folk and traditional medicines) and scientific research(phytochemical analysis) can be adopted to explore the valueof herbal preparations Based on the experience from randomtrials and observations in animals ancient people acquiredthe knowledge of using herbs for treating illness In thisconnection Chinese herbal medicine (CHM) and Indianherbal medicine (IHM) which were highly developed inancient China Japan Korea and India are still influencingthe modern healthcare [20] The World Health Organization(WHO) estimates that herbal medicines provide primaryhealthcare for approximately 35 to 4 billion people world-wide and about 85 of traditional medicine involves the useof plant extracts [21] which may be called ldquomodern herbalmedicinerdquo

Plants which constitute a major component of foodstuffsin humans have formed the basis of various traditionalmedicine systems and folk medicines that have been prac-ticed for thousands of years during the course of humanhistory Until now plantsherbs are still highly esteemedall over the world as a rich source of therapeutic agentsfor the treatment and prevention of diseases and ailmentsat present more than 35000 plant species are used formedicinal purposes around the world [22] In conventionalWestern medicine 50ndash60 of pharmaceutical commoditiescontain natural products or are synthesized from them 10ndash25 of all prescription drugs contain one ormore ingredientsderived from plants [23]

It is well known that the medicinal value of herbsplantsdepends on the presence of biological active ingredient(s)with drug-like properties Recent research has identified alot of biologically active substancesingredients from bothterrestrial and marine botanicals For example by 2007 3563 extracts and 5000 single compounds from 3000 THMshave been collected in China [24] the United States hasscreened about 114000 extracts from an estimated 35000plant samples against a number of tumor systems as earlyas before the 1990s [25] The search for new drug fromplantherb has been rapidly increasing in recent few decadesand it has led to the collection of a remarkably diverse arrayof over 139000 natural products [26] All these compoundsare potential candidates for drug development During theperiod 1981 to 2006 471 of a total of 155 clinically approvedanticancer drugswere derived fromnature inNorthAmericaEurope and Japan market [27]

The practice of traditional or folk medicine relies heavilyon the use of plant-derived herbs which can be categorizedinto two major types (1) herbs which occur in databases thatprovide detail and coherent description of the history andtheory of use for example herbs used in traditional Chi-nese medicine (TCM Zhong-Yi in Chinese) and Ayurvedicmedicine and (2) herbs used in folk medicine which lackliterature information on their history and theory of useIn general herbs with a long history and theory of use inclinical settings should be more promising candidates fordrug discovery The development of modern medicine stilldraws on clinical experiences from traditional medicinesand therapies In China at least 130ndash140 new drugs either

single chemical entities extracted from herbal medicines orsynthetically modified compounds are currently in clinicaluse [11] Some examples are anisodamine [28] indirubin [29]huperzine [30] and bicyclol [31]

Traditional knowledge and experiential databases derivedfrom clinical practice are instrumental in increasing the suc-cess rate of drug discovery by reducing the time consumedmoney spent and toxicity occurrencemdashwhich are the threemain hurdles in drug development when compared withthe conventional approach adopting random screening andchemical synthesis For example goldthread (Coptis chinensisFranch) a herb being used in TCM and Ayurvedic medicinefor the treatment of inflammatory symptoms and variousinfectious disorders formore than 3000 years [32] was foundto contain berberinemdasha substance that possesses powerfulantibiotic and anti-inflammatory properties [33 34]Withoutthe information on the use of goldthread in traditionalmedicines it would have been impossible to uncover theantimicrobial and anti-inflammatory activities of berberineby random screening More importantly berberine has beenfound to produce other pharmacological actions that mayhave implications in clinical conditions such as diabetescancer depression hypertension and hypercholesterolemiaall of which have been documented in the literature ongoldthread [35] Rauwolfia alkaloids psoralens holarrhenaalkaloids guggulsterons (an herbal supplement made fromthe sap of the Guggul) mucuna pruriens piperidines baco-sides picrosides phyllanthins curcumines withanolidesand many other steroidal lactones and glycosides have pro-vided fruitful outcomes in the area of drug discovery drawingon Ayurvedic experiential databases

Herbs used in traditional or folk medicines constituteonly a small portion of naturally occurring plants Withthe advances in analytical technology and biological sciencemany bioactive chemical entities have been identified inplants or foodstuffs through phytochemical and pharmaco-logical studies For example taxol (paclitaxel) an importantanticancer drug is isolated from the Pacific Yew tree [36]Lutein isolated from marigold is known to positively affectvisual performance and help prevent cataracts [37] Lycopenefrom tomatoes is thought to prevent certain types of cancers[38] While humans have mastered the technology of drugsynthesis plants remain a good source for drug discovery Assuchmany popular drugs such as paclitaxel vincristine vin-blastine artemisinin camptothecin and podophyllotoxinwere all derived from plants and developed by pharmaceu-tical companies

To sumup ldquopredrug stagerdquo encompasses the information-driven selection of herbs or plants in the first stage of drugdiscovery from herbsplants

22 Quasidrug Stage The ldquoquasidrugrdquo stage in drug discov-ery from herbal medicine includes the preparation of ex-tracts and phytochemical groups from herbs including thediscovery of lead compounds by using modern and con-ventional research tools Phytochemical study of extractsof herbal preparations or botanicals involves isolationstructurecomposition elucidation and bioactivity evalua-tion [39] Sometimes the biological activity of an herb


Modern herbal medicine

Marketed drug

See Figure 3Traditional herbal

Folk medicines

Wild animal eating

behavior

Serendipitous events


Clinic trial

PurificationPlant cell

culture

Herb or preparation

Phytochemical groups

Hybrid

molecules

Extracts

medicine system

Practical experience

Botanical medicine

Foodstuffs

Flavonoids alkaloids

glucides glycosides volatile oils

resins phytochromes organic acids

amino acids tannins proteins

enzymes trace elements

polysaccharides mineral

salts and so forth

Quasidrug stagePredrug stage

Singlecompound

Purificationandor leadcompoundstructure

modification

Preclinicstudy

Full-drugstage

Herbal-to-synthetic

Herbal-to-herbal

Others synthetic natural ingredients herbal ingredient combined with synthetics herbal metabolitesin vivo new compounds from herb-herb interaction

Figure 2 Current approaches for drug discovery from herbal medicines

or herbal extract can be speculated on basis of thephytochemical composition Plant polysaccharides whichare polymers consisting of either mono- or disaccha-rides joined together by glycosidic bonds produce stim-ulatingsuppressing effect on immune system [40] andthe immunomodulatory polysaccharide-containing herbsincludeGanoderma lucidum (Leyssex Fr) Karst [41] Cordy-ceps sinensis (Berk) Sacc [41] andAcaı fruit [42] Flavonoidswhich are compounds with a heterocyclic ring structureconsisting of an aromatic ring and a benzopyran ring with aphenyl substituent and include flavones isoflavone flavonolsflavonones and xanthones have been shown to possessstrong antioxidant anti-inflammatory antiproliferative andantiaging activities [43 44] They are found in almost allplants and some of them may be used for amelioratingcardiovascular mood problems and cancer [45 46] Aminoacids and proteins in herbs are usually regarded as naturalnutritional supplements for patients recovering fromdiseases[47]

Following harvesting portions of the herbplant that areused as herbs (leaves bark roots flowers seeds or fruits)are dried either in air or using a specialized industrial drier

The dried herbs can be cut or ground into finer particlesand then extracted with either water or organic solventsat an herb to solvent ratio of 1 4 (wv) If fresh herbs areused the herb to solvent ratio is 1 1 Physical (lipid solubleversus water soluble) and chemical (heat resistant versus heatlabile) properties of the ingredients present in herbs shouldbe taken into consideration when carrying out the extractionprocess Water and organic solvent extraction is the standardtechnique in the pharmaceutical industry for the isolation ofbioactive components from materials [48 49] Steam distil-lation is used in the manufacture and extraction of essentialoils from botanical materials The hot steam forces open thepockets in which the oils are kept in the plant material andthen the volatile oils escape from them and evaporate into thesteam [50] The applications of several new technologiesmdashsupercritical carbon dioxide extraction technology mem-brane separation technology semibionic extraction methodmolecular distillation technology and enzyme method inextracting effective components of medicinal plants such asTHMmdashhave been induced in the pharmaceutical industry[51ndash54] Figure 3 shows the currentmethods of herbal extrac-tion


In traditional medicines herbal remedies are mainlymade of a decoction from a mixture of raw herbs andthis dosage form is still widely used in China Japan andKorea The disadvantages of herbal decoction include (1)inconvenience in terms of usage (2) unstable in compositionand (3) issues related to quality control The deficiencies ofherbal decoctions can be overcome by using herbal extractsPlantherbal extracts including those derived from THMshave become a popular dosage form of phytomedicine andorhealth products in the globalmarket In theUSAwhile healthproducts based on plantherbal extracts constitute more than95 of market share in herbals raw herbs comprise less than5 [55]

Herbs contain hundreds of active ingredients that maybe potentially useful for the development of therapeuticagents Identification and isolation of phytochemical groupsandor single chemical entities from herbs or plant materialsare therefore crucial for drug discovery It has been esti-mated that there are at least 15 major phytochemical groupsin herbs (Figure 2) each group contains many individualchemical entities For instance flavones include more than9000 known structures [56] Alkaloids are an importantclass of active ingredient in herbsplants and more than10000 alkaloids have been isolated [57] of which morethan 80 compounds have been clinically used includ-ing berberine from Coptis chinensis Franch for bacterialinfection and inflammatory disorders [32 33] ephedrinefrom Ephedra sinica Stapf for asthma [58] reserpine fromRauvolfia verticillata (Lour) Baill previously used to treathypertension but no longer used [59] camptothecin fromCamptotheca acuminate and vincristine from Catharanthusroseus for cancers [60 61] In addition the plant secre-tions such as resins with potential application as antimi-crobial agents can also be a source of therapeutic drugsincluding haemostatic antidiarrhetic antiulcer antimicro-bial antiviral wound healing antitumor anti-inflammatoryand antioxidant [62]

The same family or genus of plants often contains thesame or similar chemical components For example bel-ladonna Solanaceae and Datura genus contain the samesubstance scopolamine The same compound can also bedistributed in different families so that berberine is notonly found in berberidaceae but also in ranunculaceae andrutaceae plants Saponins from Panax ginseng can also befound in Panax notoginseng (Burk) FH Chen another THMdistributed throughout the southwest of China Burma andNepal [63] The same bioactive ingredients may be present invarious plant parts for example ginseng leaf stem containsnumerous active ingredients (ginsenosides polysaccharidestriterpenoids flavonoids volatile oils polyacetylenic alco-hols peptides amino acids and fatty acids) and they alsopresent in the root [64 65] The same plant species can oftencontain different kinds of compounds of the same class forexample there are 25 and 70 kinds of alkaloids identified inraw opium and vinca respectively [66]

In summary the aim of the quasidrug stage of drugdiscovery from herbal medicines is to search for an activeherbal ingredient or lead compound from herbs or plantmaterials for further drug development It is well known

that the prodrug design is an extremely challenging task forchemists in the synthesis of potential therapeutic agents

23 Full-Drug Stage Nowadays drugs have become a dailynecessity for many people especially the elderly with mul-tiple health problems In China for example there are187518 kinds of home-manufactured drugs 8492 kinds ofimported drugs and 1489 patent-protected products of THM(Chinese patent medicine Zhong-Cheng-Yao in Chinese)in the pharmaceutical market and 8409 drug candidatesare now undergoing clinical trials [67] In addition in the2005 Chinese Pharmacopoeia 582 herbal medicines areofficially recognized and described In fact there are about13000 herbs and over 130000 prescriptions currently usedin various traditional medicines in China [68] In USA2900 chemical entities are currently under research anddevelopment including agents to be used in the treatmentof cancer (750) cardiovascular diseases (312) diabetes (150)AIDS (109) and Alzheimerrsquossenile dementia (91) [69]

Multinational pharmaceutical companies typically spendan annual amount of US$ 110 billion in an attempt to discovernew drugs from herbal medicine In 2003 the 10 largest phar-maceutical companies spent US$ 054 billion on research anddevelopment of THM and the American AIDS PreventionCenter conducted studies on screening more than 300 kindsof herb for anti-AIDS activity In 2002 Novartis announcedthat 500 compounds derived from THMs would enter thepatent application process [70] At present the developmentof herbal medicines mainly remains at the quasidrug stagein China (ie to develop modern herbal medicine) whilemultinational pharmaceutical companies are keen to exploitthe novel drug entities (therapeutic agents) from herbal orplant extracts In this regard current approaches in thedevelopment of herb-derived chemicals for therapeutic useare described in detail in our previous review articles [11 12]

In particular pharmaceutical chemists are interestedin hybrid molecules consisting of two distinct drug enti-ties covalently linked in a single molecule [71] such asthe hybrid of M

1muscarinic receptor agonist xanomeline

and the cholinesterase inhibitor tacrine [72] The hybridmolecule may contain natural-to-natural such as tanshinol-borneol ester [73] natural-to-synthetic such as HArsquo(10)-tacrine [74] or synthetic-to-synthetic components Protein-protein hybrid may also be possible in bioharmceuticals[75] Because of the high potential of naturally occurringcompounds in producing pronounced biological activitiesthey have become a major source of components usedfor constructing hybrid molecules in the development ofanticancer agents antioxidants and antimalarial drugs [76]Since ancient time multicomponent herbal formulae havebeen adopted in the herbal medicines For example thereare mixtures of tea known as jamu containing 30 differentkinds of plant species in Indonesia [77] Over three-quartersof sicknesses are normally treated with jamu in this countryIn this regard the herb-herb interaction in multicomponentherbal formulae may create novel chemical entity such ashybrid molecule(s)

The direct approach in drug discovery from herbalmedicines is to isolate active ingredient(s) from the respective


Herbal extracts

Dry herb

New techniques

Microwave extraction

Conventional techniques

Water extraction

Fresh herb

Supercritical fluid extraction

Heat-resistantcomponents

Organic solventextraction

Fat-solublecomponents

Water-solublecomponents

Heat-labilecomponents

Semibionicextraction

Steam distillation

Enzyme method

Figure 3 Current extraction techniques for herbal medicines

herbs or plant sourceWhether or not this approach is feasiblemainly depends on (1) the concentration of the bioactivecomponent(s) in the herb or plant (2) the degree of difficultyin purification and (3) the availability of the herb or plant inparticular whether the plant is an endangered species

3 Typical Examples of Drug Discovery fromHerbal Medicine

Antimalarial drugs developed from Artemisia annua (Qing-Hao in Chinese) and therapeutic agents for the treatmentof hepatitis developed from the fruit of Fructus schisandraechinensis (FSC) (Wu-Wei-Zi in Chinese) are the typicalexamples of successful drug discovery fromherbalmedicinesThese remarkable achievements in research and developmentof THM have received worldwide acceptance

31 Antimalarial Drugs Malaria which is currently the mostprevalent and devastating infectious diseases is a mosquito-borne infectious disease of humans caused by eukaryoticprotists of the genus Plasmodium It affects nearly 40 ofthe global population and approximately 3 billion people in109 countries [78 79] Malaria causes more than one milliondeaths worldwide each year over 90 of them occur inAfrica [80] Cerebral malaria has a mortality rate as highas 20 which can rise to 50 in pregnancy and severemalarial anemia can have a mortality rate of over 13 [81]Surviving patients with cerebral malaria with more than575000 cases annually (children in sub-Saharan Africa arethe most affected) have an increased risk of neurological andcognitive deficits behavioral difficulties and epilepsy [82]Currently chemotherapy remains the mainstay of interven-tional strategy in malaria control

Archaeological findings from Mawangdui Han DynastyTombs from200BC indicated that the herbQing-Haoderivedfrom Artemisia annua has been used in herbal remediesfor ldquolingering heat in joints and bonesrdquo and ldquoexhaustiondue to heatfeversrdquo in China for over two thousand yearsThe use of Qing-Hao for treating malaria dates back to thefourth century [83] Ge Hong a famous physician in TCMdescribed a herbal prescription against ldquointermittent feversrdquo(malaria) in one of his written works In essence fresh plantmaterials of Qing-Hao were soaked in cold water and thensqueezed for juice for oral intake [83] Qing-Hao is nativeto temperate Asia including Korea Japan Vietnam (north)Myanmar India (north) and Nepal Interestingly there arefive kinds of Qing-Hao in nature namely Artemisia apiacea(香蒿) Artemisia parviflora (小花蒿) Artemisia capillaris(茵陈蒿) Artemisia japonica (牡蒿) and Artemisia an-nua (黄花蒿) However only Artemisia annua containsartemisinin an active antimalarial ingredient [84]

Artemisinin also known as Qinghaosu in Chinese is ahighly oxygenated sesquiterpene Unlike most other anti-malarials artemisinin contains a unique 124-trioxane ringstructure which is responsible for its antimalarial activity [8586] Naturally occurring artemisinin is insoluble in water andoil with poor oral bioavailability (8ndash10) that limits its effec-tiveness [87] Reduction of the lactone in dihydroartemisininand artemether has led to increased oil solubility whereasthe acidic moiety lends water solubility to artesunate [8889] Consequently artemisinin derivatives such as dihy-droartemisinin artemether and artesunate are developedand being used around the world as effective antimalarialdrugs including those targeted against multidrug-resistantPlasmodium falciparum [90] These derivatives appear tobe more potent than the parent compound and the mostrapidly acting among all other antimalarial agents [91]


Molecular approaches in optimizing artemisinin derivativesare summarized in Figure 4 [92]

The bioavailabilities following oral administration ofdihydroartemisinin artesunate and artemether are 85 82and 54 respectively [87] 120573-Artemether an oil-soluble ethylether derivative of dihydroartemisinin consists primarily ofthree substituted ring systems fused together [93] Second-generation semisynthetic artemisinin derivatives and fullysynthetic antimalarial endoperoxide drugs have been devel-oped [94ndash96] The research on Qing-Hao not only involvesthe development of antimalarial drugs (see Figure 5) butalso explores its potential use in anticancer antiangiogen-esis antiviral immunosuppressive and antifungal therapy[97]

32 Liver Protective Agents Hepatitis an inflammatory dis-ease of the liver is commonly caused by drug intoxication orviral infection with the latter being classified into types A BC D and E According to WHO 2 billion people worldwidehave been infected by the hepatitis B virus (HBV) and amongthem 350ndash400 million are chronic HBV carriers and about1 million deaths are caused by HBV infection every year[98] It is estimated that around 12 million and 32 millionpeople in the USA are battling chronic hepatitis B and Crespectively and more than 85000 new cases of hepatitis arediagnosed each year [99] In China there are 93million HBVcarriers and among them30million are patientswith chronichepatitis B [100]

Bicyclol which was approved in 2001 as a therapeuticagent for hepatitis in China has obtained patent protectionin 15 countries and regions [101]The development of bicyclolhighlights drug discovery from THM FSC Chinese mag-nolia vine fruit or orange magnolia vine fruit in Englishis a commonly used THM According to TCM theory FSCpossesses five kinds of flavors namely pungent sweet sourbitter and salty which bespeak much of its theraputic poten-tial Two kinds of Wu-Wei-Zi Bei-Wu-Wei-Zi (Schisandrachinensis (Turcz)) and Nan-Wu-Wei-Zi (Schisandra sphenan-thera Rehd et Wils) were first recorded in Shen-Nong-Ben-Cao-Jing (Shennong Emperorrsquos Classic of Materia Medica)compiled in the first century AD Only the former is widelyused in clinical practice as an herb with a broad profileof therapeutic actions including antitussive antiasthmaticsedative and antihepatitis and tonic actions [102ndash104]

In the 1970s it was found that FSC in a dosage formof powder or bolus could decrease serum alanine amino-transferase (ALT) activity and improve symptoms in patientssuffering from viral hepatitis Experimental investigationsalso demonstrated the hepatoprotection afforded by FSCagainst chemical toxicant-induced injury in rodents [105]Activity-guided fractionation of the ethanol extract of FSCresulted in the isolation and identification of a series ofactive dibenzocyclooctadiene derivatives that could suppressserum ALT activity in animal models of hepatitis [106 107]Their relative potencies in serum ALT suppressive activityare in a descending order schizandrer B gt schizandrol B gtschisandrin C gt schisandrin B gt schisandrin A gt schizandrer

A gt schizandrol A [108] Schisandrin C which has anintermediate potency among other dibenzocyclooctadienederivatives in lowering serum ALT was selected for drugdevelopment Because the synthesis of schisandrin C was dif-ficult [109] bifendate a synthetic intermediate of schisandrinC was chosen for further investigation as a drug candidate[110ndash112]

Bicyclol a second-generation synthetic antihepatitisdrug on the market is synthesized based on bifendate It hasbeen shown to be more potent than bifendate in protectingagainst liver injury caused by toxicants or viral infection andpreventing liver fibrosis [113ndash115] Furthermore it has beenfound that the hepatoprotective action of (minus)-bicyclol wastwo times more potent than that of the racemic bicyclol andthe potency of (+)-bicyclol was much less than that of theracemate [116] In addition two metabolites of bicyclol invivo were identified and chemically synthesized but theirhepatoprotective activity was lower than that of bicyclol[117] The drug development process of FSC is summarizedin Figure 6 In addition it has recently been found in ourlaboratory that FSC and its related synthetic compounds canaffect the lipid metabolism including an increase in serumandhepatic triglyceride levels aswell as liverweight in normalmice but a decrease in liver lipids in hypercholesterolaemicmice (see Figure 7) [118ndash125] Schisandrin B inhibits FFA-induced steatosis in L-02 cells by at least in part reversingthe upregulation of ADRP and SREBP-1 [126]These findingsthus open a new avenue for FSC research

4 Systems Pharmacology and Drug Discoveryfrom Herbal Medicine

The typical drug development process from herbal medicinesincludes at least four differential aspects (1) isolation or arti-ficial synthesis of bioactive ingredient(s) in herbal medicines(2) evaluation of safety and efficacy using systems phar-macological methods (3) evaluation of safety and efficacyby means of conventional pharmacological methods and(4) regulatory approval of the therapeutic agent to be usedin the market and postmarket monitoring This conceptis illustrated in Figure 8 Here the impacts of systemspharmacology on drug discovery from herbal medicines arediscussed

41 Database in Network Systems pharmacology a newemerging field uses both experiments and computationalanalysis of regulatory networks to develop new understand-ing of drug action across multiple scales of complexityranging from molecular and cellular levels to tissue andorganism levels [127] It enables drug discovery from bothnatural remedies and synthetics andmakes predictions aboutthe possible therapeutic effects and adverse events includingpossible off-target effects through combination of the struc-tural analyses with analysis of regulatory networks [128 129]It seems to be clear that systems pharmacology providesnew approaches for drug discovery for complex diseasessuch as cancer diabetes and heart diseases Over the pastdecade genomic proteomic and metabolomic technologies


Artemisinin

Derivatives of a single active group

Derivatives of dual-active groups

Benzene-dimer derivatives

PEG-dimer derivatives

Heteroatom replace C-10-O derivatives

Ester derivatives

Ether derivatives

Alkyl ether

Aromatic ether

O-aminoether

Unsaturated-dimer derivatives

Figure 4

network analysis and other high-throughput studies as wellas structural and biochemical studies have provided a wealthof information for integrated systems-level analysis of drugaction and molecular targets including the beneficial andadverse effects for humans [130 131]

It is well known that drugs are designed to treat specificpathophysiological conditions by interacting with specifictarget(s) and cause a change of either excitement (positiverespective) or suppression (negative response) It may berecorded as the initial insight on the molecular mecha-nisms of drug action After understanding the structureof compounds from herbal medicines one can estimatetheir potential pharmaceutical value and adverse effects viasystems pharmacological analysis

Potential Drug Target Database (PDTD) a comprehen-sive andweb-accessible database of drug targets has collected1193 protein entries with 3D structure covering 831 knownand potential drug targets in the Protein Data Bank (PDB)[132ndash135] Drug targets of PDTD were categorized into 15and 13 types according to two criteria therapeutic areas andbiochemical criteria [132] By 2000 only about 500 drugtargets had been reported [136 137] among which only 120drug targets are actually marketed [138] Until 2009 howeverPubChem a public repository of small molecules and theirbiological properties contains over 1700 biochemical andcell-based bioassay screens nearly 60million biological activ-ity outcomes for different protein and gene targets whichprovide biological annotations for more than 750000 uniquesmall molecule chemical structures and tens of thousands ofsiRNA probes By 2010 the BioAssay database is comprisedof more than 2700 bioassays associated with more thanone million compounds tested against several thousandmolecular targets [139] Currently it contains more than 25million unique chemical structures and 90million bioactivity

outcomes associated with several thousand macromoleculartargets [139]

About 3700 unique entries in the Online MendelianInheritance in Man (OMIM) which is a comprehensiveauthoritative and timely compendium of human genes andgenetic phenotypes constitute the diseasome The databasealso covers a tiny fraction of the proteome consisting ofapproximately 100000 proteins [128] World of MolecularBioAcTivity (WOMBAT) [140] a leading small moleculechemogenomics database and the standard of quality insmall molecule bioactivity annotations contains 322638entries (263187 unique SMILES) totaling over 798595700biological activities on 1966 unique targets so far [140141] A bipartite interaction network has been constructedusing 1284 known disorders and 1177 known disease genesfrom the OMIM database [128] There are more than14000 targets on the DrugBank database website [142 143]This database contains 6796 drugs including 1437 FDA-approved small molecule drugs 134 FDA-approved biotech(proteinpeptide) drugs 83 nutraceuticals and 5174 experi-mentalinvestigational drugs

Currently herbal medicines are applied widely andresearchers have growing interest in scientific proof andmolecular analysis of herbal effects Therefore several herbalmedicine databases containing abundant scientific dataunderlying the use and study of herbs for health have beenadopted for using in the Internet For example the herb infor-mation knowledge base (THINKherb) database an inno-vative herb database to provide integrated and knowledge-based information contains 499 herbs 1238 genes involvinghuman mouse and rat 825 diseases 245 pharmacologicalactivity and 373 signaling pathways (human 148 mouse 121and rat 104) [144] Traditional Chinese medicine informationdatabase (TCM-ID) currently contains information for 1588


Oral andinjectable

Oral andsuppository

Injectable

ArtemisideArtemisone

H

H

H

OO

O

O

O

O

O

OH

H

H

H

OO

O

O

O

H

H

H

OO

O

O

O

H

H

H

OO

O

O

O

O

O

OO

H

H

H

OH

O O

X

O O

X

O OR

O

O

O O

O

OZ01 X= OST03 X = OCH2


OZ78 R = CH2COOHOZ209 R = CH2NH2OZ288 R = 4-OHCH6H5

NP17 NP18

Artemisia annua (Qing-Hao)

Predrug

Quasidrug

Artemisinin (Qinghaosu)

Artesunate(bioavailability 82)

Insoluble in water

Insoluble in oil

Bioavailability 8ndash10

First-generation derivatives

Dihydroartemisinin(bioavailability 85)

Full-drug

Artemether(bioavailability 54)

(bioavailability 32)

Synthetic cyclic peroxides102103

O

O

OO

H

H

N

SO O

O

O

H

H

N

S

Compounds artemetherbenflumetol tablet dihydroartemisininpiperaquine phosphate tabletdihydroartemisininpiperaquine phosphatetrimethoprim tablet

OO

120573-arteether

Second-generation derivatives100101

Figure 5 Antimalarial drugs derived from Artemisia annua a Chinese herb

prescriptions 1313 herbs 5669 herbal ingredients and the3D structure of 3725 herbal ingredients [145]The value of thedata in TCM-ID was illustrated by using some of the data foran in silico study of molecular mechanism of the therapeuticeffects of herbal ingredients and for developing a computerprogram to validate herbal medicine multiherb prepara-tions [146] Traditional Chinesemedicine integrated database

(TCMID) records sim47000 prescriptions 8159 herbs 25210compounds 6828 drugs 3791 diseases and 17521 relatedtargets [147] TCHMID displays a network for integrativerelationships between herbs and their treated diseases aswell as the active ingredients and their targets Indian PlantAnticancer Compounds Database (InPACdb) is unique inproviding comprehensive information on phytochemicals of


Bicyclol

O

OO

OO

O

Br

Br OO

OO

O

OO

O

O

O

O

O

O

O

O

O

O

O

O

H

PredrugQuasidrug

Ethanol extract (Wurenchun tabletscapsules)

Schisandrin A B C schizandrol A B schizander A B(dibenzocyclooctadiene derivatives)Hepatoprotective action

Full-drug

Schisandrin C Bifendate

Tablets relative bioavailability 237

Pills relative bioavailability 126

998400-methoxy-565998400 6998400-bis(methylenedioxy)-2-hydroxylmethyl-2998400-methoxycarbonyl biphenyl

4998400-Hydroxy-4-methoxy-565998400 6998400-bis(methylenedioxy)-2-hydroxylmethyl-2 998400-methoxycarbonyl biphenyl)

Metabolites (synthetics)

Bifendate synthetic intermediate of schisandrin C(dimethyl-44998400-dimethoxy-565998400 6998400-dimethylene-dioxybipheny1-22998400-dicarboxylate)

Bicyclol synthetic dibenzocyclooctadiene derivative(44-dimethoxy-565998400 6998400-dimethylene-dioxy-2-hydroxymethyl-2998400-carbonyl biphenyl)

Fructus schisandrae chinensis

4-Hydroxy-4

Figure 6 The discovery of therapeutic agents for hepatitis from Fructus Schisandrae chinensis (FSC) a Chinese herb

Indian origin with anticancer activity via 32 descriptive fields[148 149] Figure 9 shows these databases that will help us tofind new drugs from herbal medicines

The completion of human genome and numerous pathol-ogy-related genomes suggests that many of the 30000 to40000 identified proteins are potential targets for drug

discovery [150] It has been estimated that there are morethan 2000 potential drug targets with at least one drug can-didate in clinical trial [150 151] At present these databaseshave become a valuable resource for drug developmentand attracted considerable interest from researchers in bothacademia and industry As to how these known targets can


Normal mice treated with schisandrin B at high dose

Hepatomegaly

Schisandrin B Hypercholesterolaemic mice

HepatomegalyHepatic cholesteroltriglyceride was decreased

IG

IG

Bicyclol

Bifendate

Extracts of

FSC

Plasma turbidity

uarr Serum triglycerideuarr Hepatic triglyceride

darr Hepatic cholestrol

Figure 7 The discovery of Fructus schisandrae Chinensis (FSC) for modulating lipid metabolism

be utilized to screen drug candidates derived from herbalmedicines for disease treatment as well as to discover thenew use of an old drug present a challenge for pharma-ceutical industries and biotechnology companies Currentlythe synthetic drug is designed with reference to the three-dimensional structure of disease andor biological targetspresented in various databases Conversely a drug-like smallmolecule from herbal medicines is usually regarded as ligandfor screening related target(s) from both biological and dis-ease data sets Further researchwill be guided by the informa-tion obtained through systems pharmacology Undoubtedlysystems pharmacology will greatly expedite the developmentof therapeutics particularly for complex diseases

42 Problematics Despite the fact that systems pharmacol-ogy offers a powerful new approach for drug discovery in thepreclinical phase the research and development (RampD) effortrequired for a drug to proceed from clinical trials to marketinvolves a large amount of time and money [152] This mightbe due to the following reasons

Firstly at present although a lot of diseasedrug targetsincluding about 3700 genesproteins associatedwith diseaseshave been identified only a few drug targets are successfullyused in current therapies [153] and about two-thirds of drugsthat are currently used in the world do not target a geneproduct that has been associated with a disease Nearly 50of drugs fail in Phase III trials due to the lack of efficacy ordemonstrated benefit as compared to a placebo or an activecontrol or as an add-on therapy There are more than 1500drugs approved by the FDA but only approximately 400unique proteins are targeted by these approved drugs [128]Many biomarkers also known as targets are proposed inhighly cited studies as determinants of disease risk prognosisor response to treatment but only a fewof themare eventuallytransformed into clinical practice [154]

Secondly single andor multitargets cannot representthe individual and the mechanism of drug action at thewhole body or in vivo condition Currently for examplethe large amount of information amassed over the yearsfrom biochemical and cell-biological studies has indicated

that single-targetgene disorders are rare and most diseasesare associated with multiple genes and some diseases areassociated with 30 to 50 genes or more than 100 genesMost genetic diseases are caused by the concerted action ofmany target andor genetic abnormalities and they includemetabolic syndrome [155 156] cancers [157] hypertension[158] andmental illness likeMajorDepressiveDisorder [159]Post-Traumatic Stress Disorder [160] schizophrenia [161]AD [162] and inflammatoryinfectious diseases like arthritis[163] and AIDS [164] Furthermore a disease target may havemany family members Compounds cannot simultaneouslyaffect all disease-associated targets at gene protein andother biomarker levels Therefore ldquomagic-bulletrdquo therapy toguide the treatment of disease and drug development hasnot demonstrated a high success rate even though antisensedrugs (referred to as ldquomagic bulletrdquo) are used for the treat-ment of various conditions such as diabetes hypertensionand autoimmune and cardiovascular diseases [165 166]

Thirdly complex diseases have multiple disease andortherapeutic targets including genes enzymes ion channelstransporters receptors binding protein structural proteinssignaling proteins factors regulators and hormones alongwith other possible nontargeting factors such as environ-mental cultural social educational and climatic factorshormone levels age weight and lifestyle factors includingdietThese nontargeting elementsmay control andormodifythe function and structure of diseasedrug targets evengene expression in vivo These determinant factors dictatedisease manifestation and drug effectstoxicity including off-target effects Unfortunately this point is often overlookedin medicinal science studies Here stroke is regarded as anexample to illustrate the importance of nontarget factors inthe disease and drug effects Approximately 500000ndash600000Americans suffer stroke every year which is the third leadingcause of death and number one cause of permanent disabilityin the USA [167] Therefore the research and developmentof therapeutic agents for stroke management have attractedmuch attention So far many stroke-related and therapeutictargets have been identified at various levels as well as over500 treatment strategies in animal models of stroke including


Newly approved therapeutic agent

Safety Efficacy

Safety Efficacy

1

2

3

4

Hybrid molecules Isolation from herbs

Pharmacodynamics Pharmacokinetics

Disease datasetsBiological datasets

Conventional pharmacology

Systems pharmacology

Drug-like small moleculefrom herbal medicines

Synthetics

Toxicology

Figure 8 Current processes in drug discovery from herbal medicines

gene therapy as a novel pharmaceutical intervention [168169] However if animals are cooled (lt35∘C) infarct volumewas reduced by about one-third and the outcomes wereimproved in animal model of stroke [170] On the contraryhyperthermia has consistently been shown to increase infarctvolume in animal models of focal cerebral ischemia [171]These findings suggest that cool condition which can turn offall stroke-related targets like therapeutics has considerablepotential as a neuroprotective strategy in patients with acutestroke [171 172] It directs to a more integrated approach forhealth care than the isolation of single molecules for specifictargets for drugs In addition the enhanced longevity of theJapanese may be related to the relative late expression of theaging gene which in turn may be related to the Japanesediet andor lifestyle The nontargeting factors may thereforeinfluence the manifestation of target function

Finally many drugs particularly those derived fromnatural products hit multiple targets each of which existswithin a complex network As such approximately 35 ofknown drugs or drug candidates are active against morethan one target [173] One drug molecule may interact withseveral targets that contribute to the overall effectiveness ofa treatment including targets associated with toxicity Forexample curcumin a polyphenol natural product isolatedfrom Rhizoma Curcumae Longae at least has ten moleculartargets associated with anticancer antiviral antiarthriticantiamyloid antioxidant and anti-inflammatory properties[174] Nexavar an orally active multikinase inhibitor wasoriginally designed to inhibit Raf kinase isoforms for treating

renal and liver cancers but it was also found to inhibitPDGF and VEGF receptor tyrosine kinases [175] Thereforethe anticancer action of Nexavar involves at least threetargets including the suppression of cancer cell proliferationby inhibiting Raf and the prevention of tumor progressionand angiogenesis by inhibiting PDGFR and VEGFR If bothtargets reported in the literature and predicted targets aretaken into account there are 63 targets per drug [176] Thiscan lead to multiple outcomes ascribable to both beneficialand harmful effects of the drug

43 Some Thoughts Current drug RampD is complementedby a growing volume of bioinformatics information on thedrug candidate to ensure a high success rate in clinic trialsby predicting adverse drug reactions and efficacy in theearly stage of drug development However many drugs stillfailed at the Phase III stage meaning that the drugs couldnot show a statistically significant improvement in efficacyincluding toxicity This problematic situation indicates thatnew strategies are necessary for drug discovery

By the time new drugs are made to Phase III trial 66of them failed due to the lack of efficacy that is no sig-nificant difference between the placebo and drug treatmentor between drug and current treatment alternative and 21failed because of safety concerns [177] The high failure rateof drugs in clinical trials indicates that a variety of drugtargetsmake no sense in clinical trialsThose drugs that failedin clinical phase have gone through a lot of target researchin preclinic phase including animal safety and effectiveness


Available Databases in Drug Discovery

DrugBank

BioAssayPubChem

Online Mendelian Inheritance in Man (OMIM)

World Molecular Bioactivity

(WOMBAT)

Traditional Chinese medicines integrated

database (TCMID)

Therapeutic TargetsDatabase (TTD)156

Indian plant anticancercompounds database

(InPACdb)

Herbal MedicineDatabases

Potential Drug TargetDatabase(PDTD)

Traditional Chinesemedicine informationdatabase (TCHM-ID)

The herb informationKnowledge base(THINKherb)

Figure 9 Available databases in drug discovery

evaluation at molecular target levels which are published inreputable journals

In contrast to systems pharmacology conventional phar-macology mainly evaluates the potential efficacies and sideeffects of drug candidates under experimental and clinicalinvestigations Systems pharmacology is a virtual sciencebased on datasets supported by genomics proteomics andmetabolomics and so forth in the network but conventionalpharmacology is a practical science based on experimentalstudies Effects of drug in vivo are controlled by a complicatednetwork of targets including the biochemical and functionalresponse (signals) resulting from the interaction of drug andtarget(s) Conclusions obtained by virtual science are oftenfar from the facts for example about 90 of real off-targeteffects cannot be predicted and excluded by bioinformatics[178] Even though the diseasedrug target(s) molecularmechanism is known the effectiveness of the drug in clinictrial cannot be guaranteed

Analyzing the signaling network involved in a drugaction within the context of a patientrsquos genetic backgroundmay be critical to the success of the therapy but it is nottranslated directly to effectiveness in clinical conditionManybiologically active molecules are very active in vitro butnever reach the clinical stage There is always a discrepancybetween theory and practice particularly in medicinal sci-ence For example 120573-lactamase-producing bacteria whichcan degrade 120573-lactam antibiotics and render antibioticsinactive in inhibiting bacterial cell wall synthesis can beovercome by the combined use of 120573-lactamase inhibitors and120573-lactam antibiotics [179] However an estimated numberof 25000 patients have died of bacterial infections that areresistant to antibiotic treatment every year in hospitals ofthe European Union region [180] In 2005 almost 19000people in the USA died from an infection called methicillin-resistant Staphylococcus aureus (MRSA) [181] Therefore theeffectiveness in clinical use is the only way to determine the

validity of results obtained from basic study in therapeuticand medicine

There are thousands of chemical entities in human bodyand most of them can either be disease or drug target oreven both They may be considered as first-order diseasedrug targets second-order diseasedrug targets positivediseasedrug targets negative diseasedrug targets criticaldiseasedrug targets supplementary diseasedrug targetsand nondiseasedrug targets For disease emergence andintervention the target(s) may be either blocked or activatedby disease-causing factor and therapeutic agents In theoryonce targets on disease or pathogen are identified candidatedrugs can be obtained by selecting existing drugs or bydesigning the candidate drug at the molecular level witha computer-aided design program Although more andmore diseases and pathogen targets are revealed the successrate of new drug RampD has become lower than ever Thetreatment of modern disease has also become increasinglydifficult and sometimes patients have to be left helplessnessWhile the identification of disease and drug target isimportant the determination of interrelationship amongtargets is crucial for drug development Life science is astudy of interrelationships among cells tissues and organsPhysiological processes in human body are regulated by acomplicated network of signaling pathways Hypotheticallyeach physiological component of the network is representedby a node and each interaction is represented by an edgebetween two nodes [182 183] In a disease system thesignaling network underlying the pathological symptoms ismost likely perturbed at more than one point (node or edge)

Due to the increased incidence of complex and refrac-tory diseases with multiple targets at present combinationtherapy (ie simultaneous administration of two or moremedications to treat the same disease) based on insightobtained fromgenomic studies is very commonUp to Febru-ary 2010 the number of clinical trials for drug combinations


Pathogenomics

Bioinformatics

Transcriptomics

Environmental genomics

Proteomics

Pharmacogenomics

Functional genomics

Synthetic biologyMetabolomics

Cancer genomics

Toxicogenomics

Ecotoxicogenomics

Nutrigenomics

Interactomics

Epigenomics

Environmental proteomics

Are

peo

ple g

enes

Structural genomics

Promote the drug R and D

PGE

Promote awareness of life

Figure 10 ldquoPostgenomicrdquo era (PGE) and the associated new disciplines of study

in USA (6720) accounted for approximately 15 of thetotal number of clinical trials (44832) [152] The combi-nation of subcutaneously administered pegylated interferonand oral ribavirin is the FDA-approved regimen for thetreatment of chronic HCV infection [184] Hypolipidemicdrug combinations include statins with cholesterol esterprotein inhibitors niacin fibrates or fish oil and fibrate-ezetimibe combination [185] Herbal products have a lotof active compounds that interact with multiple targetssimultaneously Moreover the drug derived from herbalmedicines possesses polypharmacological effects in vivo Forexample natural compounds for the treatment and preven-tion of ischemic brain injury produce multiple actions suchas antioxidation anti-inflammation calcium antagonizationantiapoptosis and neurofunctional regulation [186] Becauseof the coevolution of humans and plants in nature the plant-derived components of herbal medicine should have moreaction targets than those of synthetic drugs This may bethe background of the use of herbal medicine multitargetapproach of a disease

5 Five Issues of Drug Discovery fromHerbal Medicine

On June 26 2000 it was announced by the InternationalHuman Genome Project that a working draft of the sequenceof the human genomemdashthe genetic blueprint for a humanbeingmdashwas assembled [187] Since then human historyhas entered a new eramdashthe ldquopostgenomicrdquo era So far the

elucidation of the human genome has given rise to morethan a dozen new related disciplines of study (see Figure 10)The impact of the ldquopostgenomicrdquo era on drug discovery fromherbal medicine is discussed in the following

Firstly in this ldquopostgenomicrdquo era the screening of herbalingredients should be accelerated Due to the developmentof related disciplines in the ldquopostgenomicrdquo era the pace ofdrug discovery from herbal medicine is likely to be hastenedand become more efficient than ever with a resultant highersuccess rate Unlike synthetic drugs drugs derived fromherbal medicine are developed by isolating and identifyingthe active chemical entities in the crude herbal extractrather than by going through processes of drug design andsynthesis Although many aids and tools for advanced drugdesign are now available and the in vivo properties of adrug can also be predicted using quantum mechanics andstatistical mechanics [188ndash190] the complexity of biologicalsystems often defies some of the basic assumptions of rationaldrug design As such it is impossible to estimate all drug-related parameters in an accurate manner during the ldquoprege-nomicrdquo era It is estimated that a single herbal preparationmay contain more than 100 active compounds [191] andtheir bioactivities andor drug-like properties are difficultto be accurately identified and evaluated by conventionalpharmacological methods or drug screening approaches Inaddition the levels of these compounds are exceedinglylow and usually insufficient for conducting in vivo studiesFrom 1960 to 1982 114000 crude extracts from 35000 plantsamples were processed but only two compounds taxol and


camptothecin were developed into marketable therapeutics[192]

If the endeavor had been undertaken in the ldquopostge-nomicrdquo era the success rate would likely have been muchhigher By performing a comparative study on gene expres-sion profiles before and after taking the herbal extractone can readily screen out new drug targets Furthermoregenes responsible for regulating the pharmacodynamics andpharmacokinetics of the drugs can better be understood Asa drug can cause a differential gene expression making use ofgene profiling in drug screening is an efficient way to identifythe active ingredient(s) in herbal extracts In this regarda research team at the Hong Kong University of Scienceand Technology (Hong Kong) was able to identify 23 activeingredients in Anemarrhena asphodeloides Bge (Zhi-Mu inChinese) using gene chip technology [193] which might nothave been accomplished easily by conventionaltraditionalscreening technologies

Secondly the ldquopostgenomicrdquo era should lead to theidentification of more drug targets It is well known that anydrug has its own in vivo target(s) which may be involved inthe development of a disease The Human Genome Projecthas identified 32 billion base pairs in the genome includingabout 30000 to 40000 protein-coding genes in 23 pairs ofchromosomes However the results of structural genomicsresearch can only reveal genomic structure and sequenceinformation which are only the starting point for under-standing biological function During the ldquopostgenomicrdquo erascientists will be able to create the human proteome (aninventory of all human proteins) and study the physiologicalfunction of the proteins The discovery of disease-associatedmolecular targets at the level of DNA RNA protein enzymeor receptor has made the mechanism- and structure-baseddrug discovery process obsolete Once a molecular targetof disease is revealed one can use it for identifying activeingredient(s) from herbal medicine in drug discovery Inaddition the generation of transgenic and gene knockoutanimals by biotechnological techniques can provide humandisease models for screening drugs of clinical interest forexample APOElowast3LeidenCEPT transgenic mice have beenused for screening drugs for the treatment of hyperlipidemia[194]

More often than not the etiology of a disease is multi-factorial Commonly occurring diseases such as hyperten-sion cardiovascular diseases asthma rheumatoid arthritisosteoporosis and neuropsychiatric disorders are polygenic innature For example Alzheimerrsquos disease (AD) has been char-acterized as a complex multifactorial disorder and ten AD-related genes have so far been identified [195ndash197] HuperzineA which is a drug used in the treatment of AD patientswas originally discovered from a THM Huperzia serrate[198ndash201] In addition to acetylcholinesterase inhibition ithas been shown that huperzine A also scavenges hydrogenperoxide and ameliorates beta-amyloid-induced oxidativestress and glutamate- ischemia- or staurosporine-inducedcytotoxicitycell apoptosis as well as inflammation all ofwhich are beneficial for the management of AD [198 200ndash202] With the discovery of new disease-related genes and

proteins new drug targets will become available for drugdiscovery from herbal medicine

Thirdly the ldquopostgenomicrdquo era will expand the herbalresources While scientists are deciphering genes in humansand other animals they can also do the same on plantsof interest In China projects on genome sequencing of100 animalsplants are in progress of which nearly half ofthe projects have been completed or are near completion[203] On June 20 2010 Chinese scientists announced that92 of the genome and 96 of the gene coding regionsof Salvia miltiorrhiza Bge had been elucidated [204] Theunderstanding of genomic characteristics of medicinal plantsis instrumental to generate a new variety of medicinal plantwith improved quality and efficacy

The limited supply and low concentrations of bioactiveingredients in medicinal plants have limited their usage inhealthmanagement During the ldquopostgenomicrdquo era scientistsmay obtain the desirable compounds from transgenic plantsor microbes for therapeutic applications As such the costof drug development would be reduced by the applica-tion of genetic engineering For instance China has estab-lished an Agrobacterium-mediated transformation systemforArtemisia annua and successfully transferred a number ofgenes related to artemisinin biosynthesis into the plant [205206] The genetically modified plant is capable of producingartemisinic acid an artemisinin precursor at a significantlyhigher yield than from its parent plant [207 208] Howevertransgenic plants or microbes are a very costly procedure andnot without safety risks

Fourthly a genome is not equivalent to a human bodyThe 21st century is regarded as the century of life science inrelation to genes Even though 9999 of the genes amonghumans are the same [209] individual differences exist invarious aspects of drug actionmetabolic transformation sideeffects and so forth We therefore believe that humans arenot merely genes or in other words genes are not equivalentto humans DNA RNA or proteins are not necessarily thetarget in all drugs and diseasesWe investigate the target(s) ofdrug action at the gene andor protein levels but we cannotguarantee that this drug can cure the disease or be efficaciousfor all patients Over the last 50 years more than 500000chemicals both synthetic and naturally occurring have beenscreened for antitumor activity [210] Why then does cancerstill represent such amajor therapeutic challenge In additionto the incomplete understanding of cancer development itis possible that some compounds with antitumor activityresulted from the experiments yield false-positive observa-tions during the early stages of drug discovery

According to various genome projects both mice andhumans have about 30000 genes yet only 300 are uniqueto either organism that is about 99 percent of genes inhumans have their counterparts in mice [211] About 60or more genes are conserved between flies and humansand humans have more genes than fruit flies (approximately30000 compared to 13000) [212] If genetic exchange isallowed will humans becomemice or vice versaThe answerto the question should be negative After the insertion ofa transposon into the red pigment gene morning glorybecame white rather than the expected red color [213] If


the mouse eye gene is transferred to a fruit fly can the fruitfly grow out of a pair of mouse eyes Again the answer isnegative After all genes do not govern everything in lifeTherefore conventional pharmacological methods shouldalso be incorporated into the process of drug discovery fromherbal medicine

Lastly in the ldquopostgenomicrdquo era one should not abandontradition While we acquire more in-depth understandingof the essence of life many advanced techniques for drugdiscovery have become readily available However it shouldbe kept in mind that plantsherbs which form the basis ofsophisticated traditional medicines have existed and usedfor thousands of years In addition herbs are rarely usedsingly in the practice of traditional medicines but are usuallyused in formulae of a mixture of herbs that are prescribedaccording to specific medicinal principles Moreover herbsare processed after harvest to fulfill different requirementsfor therapy dispensing and dosage forms [214] New ingredi-ent(s) may be generated from herb-herb interactions or herbprocessing

The discovery of Qinghaosu underlines the importanceof traditional knowledge in drug discovery from herbalmedicine [215 216] At first drug screening experimentsshowed that the antimalarial activity of Artemisia annuaextracts was very poor and therefore it did not arousescientistsrsquo attention for a long period of time In fact GeHong used a cold water extract of Qing-Hao rather thana decoction prepared with hot water for the treatment ofmalaria Later scientists modified the extraction method forQing-Hao by using ethanol or ether at low temperaturesA complete inhibition of mouse malaria P berghei by theQing-Hao extract derived from low-temperature process wasobserved Artemisinin a novel antimalarial drug which isheat labile was finally discovered inChinaThe success rate ofdrug development from plants based on random screening isundeniably low The story of artemisinin has emphasized theimportance of traditional information in achieving a highersuccess rate in drug discovery from herbal medicine

6 Problems of Drug Discovery fromHerbal Medicine

Strategies of drug discovery from nature resources are greatlydifferent from those of synthetics It involves two key issuesfor example ecological ethics and resource-dependent sus-tainable development

(1) The current development of herbal medicinesinvolves both modern ethics and technologies Inthis section ecological ethics on the drug discoveryfrom herbal medicine are discussed Ecological ethicsare moral principles governing human attitudestowards the environment and rules of conduct forcare and preservation of the environment [217] Onour planet no species including humans can evolveindependently of its coevolution with other speciesBy the same token no species can live independentlyof other species As the ecological environment onearth deteriorates the number of existing species has

drastically decreased over the last five decades withthe exception of the rapidly growing humans In factthe imbalance between humans and other specieshas become a threat to the survival of humansthereby ecosystem or plant ecology should be firstlyconsidered in the herbal development

(2) Plants including medicinal plants have incrediblebiological diversity showing extreme flexibility inecomorphology It is undoubtedly that plants play animportant role in ecosystems by providing essentialservices Without plants there would be no humananimals and insects in other words no life as weunderstand it on earth without plants In any casevegetation always acts as indicator of general ecosys-tem health Unfortunately to date many specieshave disappeared even before they could be iden-tified Ten years ago biologists warned that 25of all species could become extinct over the next20 to 30 years [218] Over the past two decadespharmaceutical companies have shown an increasedinterest in exploring new compounds from plantsfor drug development However the lack of a ratio-nal approach in many aspects of this undertakingincluding drug discovery from herbal medicine haslimited the success of these endeavors In 2004the World Wildlife Fund pointed out that due tothe overexploitation of human consumption 20of medicinal plants in the world are facing extinc-tion These include popular medicinal plants suchas Cypripedium pubescens Trillium erectum Aletrisfarinose Chamaelirium luteum syn Helonias lutea(dioica) Hydrastis Canadensis and Panax quinque-folius [219] as well as many plants used in traditionalherbalmedicineThere are about 250000 higher plantspecies onEarth and over 80000 have goodmedicinalvalues The past experience told us that once aplant species had been identified for its commercialpotential it may face a risk of extinction

(3) In China for instance there are about thousandendangered plants of which 60ndash70 are medici-nal plants [220] There are nearly 12000 species ofmedicinal plants used in TCM and more than 6000species have disappeared over a period of less than20 years At present out of 400 kinds of commonlyused herbs the supply of more than 20 of themhas become depleted from natural sources [221] Forexample the annual sales of Isatis tinctoria L Ban-Lan-Gen in Chinese were increased from 3000 tonsin 1970s to 60000 tons during the period from 2006to 2008 [221] the over consumption of Ban-Lan-Gen has therefore depleted its supply from naturalsourceTherefore the preservation of endangered andrare medicinal plants has been an area of immenseinterest particularly in China [222 223] Due tothe market-driven overexploitation of herbal or plantresources in recent years many herbs have beenlisted (or may soon be listed) as endangered speciesChina where herbal preparations account for 30ndash50


Save the endangered

herbal medicine

Search for alternative

species

Cultivation of medicinal

plants

Control the usage

Prohibits the usage

Full use

Cell culture

Transgentic medicinal plants

Synthetic herbalingredients

Bacteria makethe active

ingredients

Figure 11 Available approaches in preserving the endangered plants or herbs used in herbal medicines

of the total medicinal consumption has a numberof herbs listed in the China Plant Red Data Bookin which the category of ldquoRare and EndangeredPlantsrdquo includes Acanthopanax senticosus Fritillariaussuriensis Aquilaria sinensis Fritillaria walujewiiAstragalus membranaceus Gastrodia elata A mem-branaceus var mongolicus Ginkgo biloba Changiumsmyrnioides Glehnia littoralis Cistanche deserticolaIllicium difengpi Coptis teeta Juglans regia CoptischinensisMagnolia officinalis Dalbergia odorifera Mo var biloba Dendrobium candidum Morinda offici-nalis Dimocarpus longan Panax ginseng Eucommiaulmoides Phellodendron amurense Ferula sinkian-gensis Picrorhiza scrophulariiflora Fritillaria pallid-iflora and Rosa rugosa [224] Many herbs fromArabian herbalmedicine includingAnchusa negeven-sis Anchusa ovata Eryngium barrelieri Eryngiummaritimum Eryngiummaritimum Euphorbia hirsuteOphioglossum lusitanicum Ophioglossum polyphyl-lum Teucrium procerum Teucrium scordium andTeucrium scordium have also been designated rare orendangered species [225]

(4) Drug development from herbal medicine should takeinto account the diversity of species and ecolog-ical ethics Ideally during the drug developmentone first isolates and identifies target compoundsfrom herbs or plants which is followed by totalchemical synthesis of the compound(s) as was thecase for aspirin When a bioactive compound hasbeen isolated modification of the chemical structuremay be performed in order to reduce the toxicityand increase the efficacy and solubility of the drugcandidate Acetylsalicylic acid also called aspirin isan acetyl derivative of salicylic acid which is derivedfrom the metabolism of salicin a naturally occurringcompound found in the bark of Willow and Spiraea

plant 150 years ago However commercially availablesalicylic acid and aspirin are synthetics [226 227]Interestingly aspirin causes a lesser degree of diges-tive upset than salicylic acid Semisynthetic deriva-tives of artemisinin isolated from the plant Artemisiaannua such as dihydroartemisinin artemether andartesunate were found to be more bioavailable andhave greater activity than artemisinin itself [228 229]However it is well known that the modification of thechemical structure of compounds derived from herbsdoes not always yield results with positive impact onthe societies such as heroin (diamorphine) and ldquoBing-Durdquo (methamphetamine) Some approaches for pre-serving rare and endangered medicinal plants areshown in Figure 11 The ethical principles should beconformed during the development and exploitationof herbalmedicineAfter all humans should not fulfilltheir own needs at the expense of other species onearth On the other hand in less developed countriesherbal medicine is the primary source of health careWhen these herbs are seized by big Pharma theresulting drugs will not be available to the peoplebecause of the costs This is also an ethical issuein drug discovery from herbal medicines Generallythe herbal medicines that are traditionally used ontheir value are less expensive than the new single-component drugs from them

(5) In order to meet the escalating demand for medicinalplants herbal agriculture or farming of these plants isimperativemdashand the development of agrotechnologyrelated to herbal production has become an area ofintensive research Farming medicinal plants (Yao-Nong in Chinese) for herb production has provided anumber of jobs in China During 2005ndash2010 centraland local governments as well as enterprises in Chinainvested 11556 million RMB for the cultivation of


herbs [230] Currently there are 250 kinds of medicalplants being cultivated or grown in China encom-passing 333 million hectares of farmland [231] As of2010 there are 99 Good Agricultural Practice (GAP)sites and 49 species of herbs are currently cultivatedat these sites [232] In Germany 19 species commonlyused in herbs have been investigated for commercialcultivation or breeding [233] In addition cell andbacterial cultures as well as transgenic plants are alsoavailable for supplying source materials for drug dis-covery from herbal medicine For instance Artemisiaannua is the commercial source of artemisinin butthe concentration of artemisinin in this herb is lowranging from 001 to 08 of the dry weight ofthe plant To meet the increasing demand in themarket transgenic plants containing a higher contentof artemisinin were developed [234] Although theuse of transgenic plants is a disputable means of pre-serving biodiversity genetic engineering will play animportant role in saving the medicinal plants whichare rare endangered or threatened with extinctionIf the precursor (mevalonic acid lactone) and elicitor(methyl jasmonate) were added to the cell culturesthe production of artemisinin was increased by about6 times relative to control cultures [235] In additionEscherichia coli can produce terpene amorpha-4 11-diene a precursor of artemisinin [236]

(6) Generally drug discovery from herbs should mainlyinvolve synthesis and cultivation of medicinal plantsnot just exploiting the wild plants in nature Fur-thermore to the largest possible extent all parts ofa medicinal plant should be utilized For exampleginsenosides the active ingredients of RadixGinsengare also found in the leaves and stems ofPanax ginseng[237 238] therefore leaves are also of medicinalvalues like stems We can only harvest the leaves ofPanax ginseng and let it grow back next year

7 Concluding Remarks

As ancient humans adopted a plant-based (ie herbivorous)diet the body function of humansmay have been primed by alarge number of secondary metabolites derived from plantsConsidering the extremely high cost and long time of newdrug development as well as the high drug attrition rate animminent task for pharmaceutical companies is to explorenew ways for drug RampDTherefore more and more attentionin the field of drug discovery has been focused on the herbalmedicine Herbalmedicine as a source of new compounds fordrugs is going to become a global trend in the pharmaceuticalindustry [239]

An impressive number of chemicals have been isolatedeither from medicinal plants or synthesized on the basisof natural lead compounds For instance schisandrin Cpresent in Schisandra chinensis has led to the discoveryand development of two potent drug derivatives bifendateand bicyclol Artemisinin isolated from Artemisia annua hasgenerated at least ten new drugs on the market Therefore

the use of herbalplant medicine has been the single mostsuccessful strategy for the development of novel therapeuticagents and this trend will be continued in the future

In an era of rapidly advancing science and technologythere is a tendency to ignore traditional values and knowl-edge as well as traditional medicines at large Although theldquopostgenomicrdquo era offers great opportunities for screeningactive compounds from medicinal plants one should beaware of traditional knowledge in an attempt to discoverdrugs derived from herbal medicine Many medicinal prop-erties of plant species were revealed from experience accu-mulated from a long history of use in many traditional herbaltherapies Knowledge accumulated in traditional medicinetherefore plays an important role in enhancing the successrate of drug discovery from herbal medicine Generallythe success rate of the synthetic route for developing newmedicinal agents may be 110000 however the success ratewith search for new therapeutic moieties based on medicalplants used in traditional medicinal system can be as high as14 or more

Last but not least the principle of ecological ethics shouldbe upheld by preserving biodiversity while exploiting naturalresources for drug discovery Man does not have the rightto wipe out any species arbitrarily and mess with genes tocreate transgenic crops for their own benefits People are justone of the residents on Earth As articulated by the ancientChinese philosopher Lao Zi ldquoMother Nature is benevolentto all living things even a stray dog on earthrdquo Modernanthropocentrism with value of philosophical significancefor sustainable development should be implemented in theprocesses of herbal medicine RampD

Conflict of Interests

The authors declared no conflict of interests with respect tothe authorship andor publication of this paper

Authorsrsquo Contribution

S-Y Pan S-F Zhou and S-H Gao contributed equally tothe work

Acknowledgments

This paper was supported by the National Natural ScienceFoundation of China (Grant no 31071989) and the Out-standing Teaching Team of Chinese Herbal Pharmacology inBeijing City (Grant no 201006)

References

[1] M Wu D Atchley L Greer S Janssen D Rosenberg andJ Sass ldquoDosed without prescription preventing pharmaceuti-cal contamination of our nationrsquos drinking waterrdquo httpdocsnrdcorghealthfileshea 10012001apdf

[2] C J Barden and D F Weaver ldquoThe rise of micropharmardquo DrugDiscovery Today vol 15 no 3-4 pp 84ndash87 2010


[3] A I Graul L Revel M Barrionuevo et al ldquoThe yearrsquos newdrugs amp biologicsmdash2008rdquo Drug News and Perspectives vol 22no 1 pp 7ndash29 2009

[4] S Kuhne ldquoThe future science buisness and innovationrdquohttpwwwsciencebusseSciencebusSebastiaanKuhne filesSEBASTIAAN20KUHNEpdf

[5] B Sibbald ldquoRofecoxib (Vioxx) voluntarily withdrawn frommarketrdquo Canadian Medical Association Journal vol 171 no 9pp 1027ndash1028 2004

[6] S Y Pan S H Gao S F Zhou et al ldquoNew perspectiveson complementary and alternative medicine an overviewand alternative therapyrdquo Alternative Therapies in Health andMedicine vol 18 no 4 pp 20ndash36 2012

[7] L C Winslow and D J Kroll ldquoHerbs as medicinesrdquo Archives ofInternal Medicine vol 158 no 20 pp 2192ndash2199 1998

[8] R Raman and S Kandula ldquoZoopharmacognosyrdquo httpwwwiasacinresonanceMarch2008p245-253pdf

[9] S Krief A Jamart S Mahe et al ldquoClinical and pathologicmanifestation of oesophagostomosis in African great apes doesself-medication in wild apes influence disease progressionrdquoJournal of Medical Primatology vol 37 no 4 pp 188ndash195 2008

[10] A Fowler Y Koutsioni and V Sommer ldquoLeaf-swallowing inNigerian chimpanzees evidence for assumed self-medicationrdquoPrimates vol 48 no 1 pp 73ndash76 2007

[11] S Y Pan S B Chen H G Dong et al ldquoNew perspec-tives on Chinese herbal medicine (Zhong-Yao) research anddevelopmentrdquo Evidence Based Complementary and AlternativeMedicine vol 2011 Article ID 403709 11 pages 2011

[12] S M He E Chan and S F Zhou ldquoADME properties of herbalmedicines in humans evidence challenges andstrategiesrdquo Cur-rent Pharmaceutical Design vol 17 no 4 pp 357ndash407 2011

[13] E Chan M Tan J Xin S Sudarsanam and D E John-son ldquoInteractions between traditional Chinese medicines andWestern therapeuticsrdquo Current Opinion in Drug Discovery andDevelopment vol 13 no 1 pp 50ndash65 2010

[14] XW Chen K B Sneed S Y Pan et al ldquoHerb-drug interactionsandmechanistic and clinical considerationsrdquoCurrentMedicinalChemistry vol 13 no 5 pp 640ndash651 2012

[15] XW Chen E S Serag K B Sneed et al ldquoClinical herbal inter-actions with conventional drugs from molecules to maladiesrdquoCurrent Medicinal Chemistry vol 18 no 31 pp 4836ndash48502011

[16] B Patwardhan A D B Vaidya and M Chorghade ldquoAyurvedaand natural products drug discoveryrdquo Current Science vol 86no 6 pp 789ndash799 2004

[17] M Gordaliza ldquoTerpenyl-purines from the seardquo Marine Drugsvol 7 no 4 pp 833ndash849 2009

[18] M Maridass and A John de Britto ldquoOrigins of plant derivedmedicinesrdquo Ethnobotanical Leaflets vol 12 pp 373ndash387 2008

[19] S Krief M T Martin P Grellier J Kasenene and T SevenetldquoNovel antimalarial compounds isolated in a survey of self-medicative behavior of wild chimpanzees in Ugandardquo Antimi-crobial Agents and Chemotherapy vol 48 no 8 pp 3196ndash31992004

[20] R P Samy P N Pushparaj and P Gopalakrishnakone ldquoAcompilation of bioactive compounds from Ayurvedardquo Bioinfor-mation vol 3 no 3 pp 100ndash110 2008

[21] N R Farnsworth ldquoScreening plants for new medicinesrdquohttpwwwciesinorgdocs002-256c002-256chtml

[22] G Yirga M Teferi and M Kasaye ldquoSurvey of medicinal plantsused to treat human ailments in Hawzen district Northern

Ethiopiardquo International Journal of Biodiversity and Conserva-tion vol 3 no 13 pp 709ndash714 2011

[23] S I Cameron R F Smith and K E Kierstead ldquoLinkingmedic-inalnutraceutical products research with commercializationrdquoPharmacetical Biology vol 43 no 5 pp 425ndash433 2005

[24] Z L Deng ldquoApplication of new techniques in the innovativeresearch of Chinese herbal medicinerdquo Chinese Pharmaceuticalvol 16 pp 58ndash589 2007 (Chinese)

[25] N Sithranga Boopathy and K Kathiresan ldquoAnticancer drugsfrom marine flora an overviewrdquo Journal of Oncology vol 2010Article ID 214186 18 pages 2010

[26] N S Boopathy and K Kathiresan ldquoAnticancer drugs frommarine flora an overviewrdquo Journal of Oncology vol 2010Article ID 214186 18 pages 2010

[27] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007

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[29] G Eisenbrand F Hippe S Jakobs and S Muehlbeyer ldquoMolec-ular mechanisms of indirubin and its derivatives novel anti-cancer molecules with their origin in traditional Chinese phy-tomedicinerdquo Journal of Cancer Research and Clinical Oncologyvol 130 no 11 pp 627ndash635 2004

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[32] X Z Zhu X Y Li and J Liu ldquoRecent pharmacologicalstudies on natural products in Chinardquo European Journal ofPharmacology vol 500 no 1ndash3 pp 221ndash230 2004

[33] C L Kuo C W Chi and T Y Liu ldquoThe anti-inflammatorypotential of berberine in vitro and in vivordquo Cancer Letters vol203 no 2 pp 127ndash137 2004

[34] D Yan C Jin X H Xiao and X P Dong ldquoAntimicrobialproperties of berberines alkaloids in Coptis chinensis Franchby microcalorimetryrdquo Journal of Biochemical and BiophysicalMethods vol 70 no 6 pp 845ndash849 2008

[35] P R Vuddanda S Chakraborty and S Singh ldquoBerberinea potential phytochemical with multispectrum therapeuticactivitiesrdquo Expert Opinion on Investigational Drugs vol 19 no10 pp 1297ndash1307 2010

[36] V Walsh and J Goodman ldquoCancer chemotherapy biodiversitypublic and private property the case of the anti-cancer drugTaxolrdquo Social Science andMedicine vol 49 no 9 pp 1215ndash12251999

[37] F Khachik A Steck and H Pfander ldquoIsolation and structuralelucidation of (13Z13rsquoZ3R3rsquoR6rsquoR)-lutein frommarigold flow-ers kale and human plasmardquo Journal of Agricultural and FoodChemistry vol 47 no 2 pp 455ndash461 1999

[38] G Lippi and G Targher ldquoTomatoes lycopene-containing foodsand cancer riskrdquo British Journal of Cancer vol 104 no 7 pp1234ndash1235 2011

[39] S Sasidharan Y Chen D Saravanan K M Sundram andL Yoga Latha ldquoExtraction isolation and characterization ofbioactive compounds from plantsrsquo extractsrdquo African Journal ofTraditional Complementary and Alternative Medicines vol 8no 1 pp 1ndash10 2011


[40] J E Ramberg E D Nelson and R A Sinnott ldquoImmunomod-ulatory dietary polysaccharides a systematic review of theliteraturerdquo Nutrition Journal vol 9 article 54 2010

[41] Z Xu X Chen Z Zhong L Chen and Y Wang ldquoGan-oderma lucidum polysaccharides immunomodulation andpotential anti-tumor activitiesrdquoTheAmerican Journal of ChineseMedicine vol 39 no 1 pp 15ndash27 2011

[42] J Holderness I A Schepetkin B Freedman et al ldquoPolysaccha-rides isolated from acaı fruit induce innate immune responsesrdquoPLoS One vol 6 no 2 Article ID e17301 2011

[43] G Leonarduzzi G Testa B Sottero P Gamba and GPoli ldquoDesign and development of nanovehicle-based deliverysystems for preventive or therapeutic supplementation withflavonoidsrdquo Current Medicinal Chemistry vol 17 no 1 pp 74ndash95 2010

[44] A R Im Y H Kim M R Uddin et al ldquoScutellaria baicalensisextracts and flavonoids protect rat L6 cells from antimycin A-induced mitochondrial dysfunctionrdquo Evidence Based Comple-mentary and Alternative Medicine vol 2012 Article ID 5179658 pages 2012

[45] D Prochazkova I Bousova and N Wilhelmova ldquoAntioxidantand prooxidant properties of flavonoidsrdquoFitoterapia vol 82 no4 pp 513ndash523 2011

[46] A K Jager and L Saaby ldquoFlavonoids and the CNSrdquo Moleculesvol 16 no 2 pp 1471ndash1485 2011

[47] J P Sheng H R Chen and L Shen ldquoComparative study onselenium and amino acids content in leaves of planted and wildscutellaria baicalensisrdquo Spectroscopy and Spectral Analysis vol29 no 1 pp 211ndash213 2009 (Chinese)

[48] J Dai and R J Mumper ldquoPlant phenolics extraction analysisand their antioxidant and anticancer propertiesrdquoMolecules vol15 no 10 pp 7313ndash7352 2010

[49] A K Sinha U K Sharma and N Sharma ldquoA comprehensivereview on vanilla flavor extraction isolation and quantificationof vanillin and others constituentsrdquo International Journal ofFood Sciences and Nutrition vol 59 no 4 pp 299ndash326 2008

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[52] Z He and W Xia ldquoMicrowave-assisted extraction of phenolicsfrom Canarium album L and identification of the main phe-nolic compoundrdquo Natural Product Research vol 25 no 2 pp85ndash92 2011

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[62] D Gupta B Bleakley and R K Gupta ldquoDragonrsquos blood botanychemistry and therapeutic usesrdquo Journal of Ethnopharmacologyvol 115 no 3 pp 361ndash380 2008

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[64] G Y Liu X W Li N B Wang et al ldquoThree new dammarane-type triterpene saponins from the leaves of Panax ginseng CAMeyerrdquo Journal of Asian Natural Products Research vol 12 no10 pp 865ndash873 2010

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[71] C Valant J Robert Lane P M Sexton and A ChristopoulosldquoThe best of both worlds Bitopic orthostericallosteric ligandsof G protein-coupled receptorsrdquo Annual Review of Pharmacol-ogy and Toxicology vol 52 pp 153ndash178 2012

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[73] X H Zheng Y C Zhang Q Z Zhang and X F ZhaoldquoSynthesis and usage of Tanshinol borneol esterrdquo Patent noZL200600427873

[74] W M Li K K W Kan P R Carlier Y P Pang and Y F HanldquoEast meets west in the search for Alzheimerrsquos therapeuticsmdashnovel dimeric inhibitors from tacrine and huperzineArdquoCurrentAlzheimer Research vol 4 no 4 pp 386ndash396 2007

[75] Y Itoh M Ishikawa M Naito and Y Hashimoto ldquoProteinknockdown using methyl bestatin-ligand hybrid molecules


design and synthesis of inducers of ubiquitination-mediateddegradation of cellular retinoic acid-binding proteinsrdquo Journalof the AmericanChemical Society vol 132 no 16 pp 5820ndash58262010

[76] M Decker ldquoHybrid molecules incorporating natural productsapplications in cancer therapy neurodegenerative disorders andbeyondrdquo Current Medicinal Chemistry vol 18 no 10 pp 1464ndash1475 2011

[77] A D Setyawan ldquoTraditionally utilization of Selaginella fieldresearch and literature reviewrdquo Bioscience vol 1 no 3 pp 146ndash158 2009

[78] FWMuregi and A Ishih ldquoNext-generation antimalarial drugshybrid molecules as a new strategy in drug designrdquo DrugDevelopment Research vol 71 no 1 pp 20ndash32 2010

[79] P M OrsquoNeill V E Barton and S A Ward ldquoThe molecularmechanism of action of artemisininthe debate continuesrdquoMolecules vol 15 no 3 pp 1705ndash1721 2010

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[81] ldquoMalaria severe life-threateningrdquo httpwwwncbinlmnihgovpmcarticlesPMC2943816pdf2007-0913pdf

[82] R Idro K Marsh C C John and C R J Newton ldquoCere-bral malaria mechanisms of brain injury and strategies forimproved neurocognitive outcomerdquo Pediatric Research vol 68no 4 pp 267ndash274 2010

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[84] ldquoQing Haordquo (Chinese) httpwwwhudongcomwikiE99D92E892BF

[85] G D Brown ldquoThe biosynthesis of artemisinin (Qinghaosu)and the phytochemistry of artemisia annua L (Qinghao)rdquoMol-ecules vol 15 no 11 pp 7603ndash7698 2010

[86] H K Webster and E K Lehnert ldquoChemistry of artemisinin anoverviewrdquo Transactions of the Royal Society of Tropical Medicineand Hygiene vol 88 supplement 1 pp S27ndashS29 1994

[87] G A Balint ldquoArtemisinin and its derivatives an important newclass of antimalarial agentsrdquo Pharmacology and Therapeuticsvol 90 no 2-3 pp 261ndash265 2001

[88] V Kumar A Mahajan and K Chibale ldquoSynthetic medicinalchemistry of selected antimalarial natural productsrdquo Bioorganicand Medicinal Chemistry vol 17 no 6 pp 2236ndash2275 2009

[89] A G Griesbeck J Neudorfl A Horauf S Specht and ARaabe ldquoAntimalarial peroxide dyads from natural artemisininand hydroxyalkylated 124-trioxanesrdquo Journal of MedicinalChemistry vol 52 no 10 pp 3420ndash3423 2009

[90] Y Li and Y L Wu ldquoHow Chinese scientists discovered qing-haosu (artemisinin) and developed its derivativesWhat are thefuture perspectivesrdquoMedecine Tropicale vol 58 supplement 3pp S9ndashS12 1998

[91] D L Klayman ldquoQinghaosu (Artemisinin) an antimalarial drugfrom Chinardquo Science vol 228 no 4703 pp 1049ndash1055 1985

[92] D D Shen Y X Zang M M Shen X C Yang and C Y HaldquoProgress in dihydroartemisinin derivativesrdquo (Chinese) httpwenkubaiducomview2e5468c6aa00b52acfc7ca98html

[93] F S El-Feraly M A Al-Yahya K Y Orabi D R McPhail andA T McPhail ldquoA new method for the preparation of arteetherand its C-9 epimerrdquo Journal of Natural Products vol 55 no 7pp 878ndash883 1992

[94] M Ramharter D Burkhardt J Nemeth A A Adegnika andP G Kremsner ldquoShort report in vitro activity of artemisonecomparedwith artesunate against Plasmodium falciparumrdquoTheAmerican Journal of Tropical Medicine and Hygiene vol 75 no4 pp 637ndash639 2006

[95] P M OrsquoNeill ldquoThe therapeutic potential of semi-syntheticartemisinin and synthetic endoperoxide antimalarial agentsrdquoExpert Opinion on Investigational Drugs vol 14 no 9 pp 1117ndash1128 2005

[96] M C Lombard D D NrsquoDa J C Breytenbach P J Smith andC A Lategan ldquoArtemisinin-quinoline hybrid-dimers synthesisand in vitro antiplasmodial activityrdquo Bioorganic and MedicinalChemistry Letters vol 20 no 23 pp 6975ndash6977 2010

[97] S Lee ldquoArtemisinin promising lead natural product for variousdrug developmentsrdquoMini-Reviews in Medicinal Chemistry vol7 no 4 pp 411ndash422 2007

[98] F M Lu and H Zhuang ldquoManagement of hepatitis B in ChinardquoChinese Medical Journal vol 122 no 1 pp 3ndash4 2009

[99] Hepatitis httpwwwmahalocomhepatitis[100] F M Lu and H Zhuang ldquoManagement of hepatitis B in Chinardquo

Chinese Medicine Journal vol 122 no 1 pp 3ndash4 2009[101] ldquoAnti-hepatitis new drug bicyclolrdquo (Chinese) httpwww5ymy

comnewsgxytj0931383html[102] A Panossian and G Wikman ldquoPharmacology of Schisandra

chinensis Bail an overview of Russian research and uses inmedicinerdquo Journal of Ethnopharmacology vol 118 no 2 pp183ndash212 2008

[103] Y Lu and D F Chen ldquoAnalysis of Schisandra chinensis andSchisandra sphenantherardquo Journal of Chromatography A vol1216 no 11 pp 1980ndash1990 2009

[104] W Xie and L Du ldquoDiabetes is an inflammatory diseaseevidence from traditional ChinesemedicinesrdquoDiabetes Obesityand Metabolism vol 13 no 4 pp 289ndash301 2011 (Chinese)

[105] T T Pao K T Liu H F Hsu and C Y Sung ldquoStudies onFructus schizandrae I Its effect on increased SGPT levels inanimals caused by hepatotoxic chemical agentsrdquo Journal ofChinese Medicine vol 5 no 2 pp 275ndash278 1974 (Chinese)

[106] Y Y Chen Z B Shu and L N Li ldquoSchisandra studymdashisolationand identification of bioactive ingredients for lowering alanineaminotransferase activityrdquo Science China A vol 1 pp 98ndash1101976 (Chinese)

[107] Y Y Chen and L N Li ldquoSchisandra studymdashdetermination ofschizander A and B structurerdquo Acta Chimica Sinica vol 34 pp48ndash55 1976 (Chinese)

[108] T T Bao G F Tu G T Liu R H Sun and Z Y SongldquoA comparison of the pharmacological actions of seven con-stituents isolated from fructus schizadrae (authorrsquos transl)rdquoActaPharmaceutica Sinica vol 14 no 1 pp 1ndash7 1979 (Chinese)

[109] J X Xie J Zhou Z Zhan J H Yang J X Chen and H QJin ldquoSynthesis of schizandrin C analogsrdquo Acta PharmacologicaSinica vol 16 no 4 pp 306ndash309 1981 (Chinese)

[110] G T Liu H L Wei and Z Y Song ldquoFurther studies on theprotective action of biphenyl dimethyl-dicarboxylate (BDD)against experimental liver injury in mice (authorrsquos transl)rdquoActaPharmaceutica Sinica vol 17 no 2 pp 101ndash106 1982

[111] G T Liu ldquoFrom the study of Fructus schizandrae to the discov-ery of biphenyl dimethyl-dicarboxylaterdquo Acta PharmaceuticaSinica vol 18 no 9 pp 714ndash720 1983

[112] X L Wang M G Yi Z M Liu and Z Y Song ldquoAbsorptiondistribution and excretion of biphenyl dimethyl-dicarboxylate(BDD)rdquo Acta Pharmaceutica Sinica vol 18 no 12 pp 892ndash8991983


[113] G T Liu ldquoThe anti virus and hepatoprotective effect of bicycloland itsmechanism of actionrdquoChinese Journal of NewDrugs vol10 no 5 pp 325ndash327 2001 (Chinese)

[114] X J Gu ldquoThe efficacy of bicyclol in treatment of chronichepatitis B Chinrdquo Chinese Journal of New Drugs vol 13 no 10pp 940ndash942 2004

[115] Y Li G W Dai G T Liu and Y Li ldquoEffect of bicyclol onacetaminophen-induced hepatotoxicity energetic metabolismand mitochondrial injury in acetaminophen-intoxicated micerdquoActa Pharmacologica Sinica vol 36 no 10 pp 723ndash726 2001(Chinese)

[116] W Hu C Z Zhang and Y Li ldquoResolution of racemic anti-hep-atitis drug (+-) -bicyclolrdquo Acta Pharmacologica Sinica vol 41no 3 pp 221ndash224 2006 (Chinese)

[117] Y TangWHu Y Li and C Z Zhang ldquoSynthesis of metabolitesof bicyclolrdquo Acta Pharmacologica Sinica vol 42 no 10 pp1054ndash1057 2007 (Chinese)

[118] S Y Pan H Dong B F Guo et al ldquoEffective kinetics of schisan-drin B on serumhepatic triglyceride and total cholesterol levelsin mice with and without the influence of fenofibraterdquoNaunyn-Schmiedebergrsquos Archives of Pharmacology vol 383 no 6 pp585ndash591 2011

[119] S Y Pan Z L Yu H Dong C J Xiang W F Fong and K MKo ldquoEthanol extract of fructus schisandrae decreases hepatictriglyceride level in mice fed with a high fatcholesterol dietwith attention to acute toxicityrdquo Evidence-based Complementaryand Alternative Medicine vol 2011 Article ID 729412 6 pages2011

[120] S Y Pan H Dong X Y Zhao et al ldquoSchisandrin B fromSchisandra chinensis reduces hepatic lipid contents in hyper-cholesterolaemic micerdquo The Journal of Pharmacy and Pharma-cology vol 60 no 3 pp 399ndash403 2008

[121] S Y Pan H Dong Z L Yu et al ldquoBicyclol a synthetic dibenzo-cyclooctadiene derivative decreases hepatic lipids but increasesserum triglyceride level in normal and hypercholesterolaemicmicerdquo The Journal of Pharmacy and Pharmacology vol 59 no12 pp 1657ndash1662 2007

[122] S Y Pan R Yang H Dong Z L Yu and K M Ko ldquoBifen-date treatment attenuates hepatic steatosis in cholesterolbilesalt- and high-fat diet-induced hypercholesterolemia in micerdquoEuropean Journal of Pharmacology vol 552 no 1ndash3 pp 170ndash1752006

[123] S Y Pan R Yang Y F Han et al ldquoHigh doses of bifendateelevate serumandhepatic triglyceride levels in rabbits andmiceanimal models of acute hypertriglyceridemiardquo Acta Pharmaco-logica Sinica vol 27 no 6 pp 673ndash678 2006

[124] S Y Pan H Dong Y F Han W Y Li X Y Zhao and K MKo ldquoA novel experimental model of acute hypertriglyceridemiainduced by schisandrin Brdquo European Journal of Pharmacologyvol 537 no 1ndash3 pp 200ndash204 2006

[125] S Y Pan Q Yu Zhang Y et al ldquoDietary Fructus Schisandraeextracts and fenofibrate regulate the serumhepatic lipid-profilein normal and hypercholesterolemic mice with attention tohepatotoxicityrdquo Lipids in Health and Disease vol 11 article 1202012

[126] J H Chu HWang Y Ye et al ldquoInhibitory effect of schisandrinB on free fatty acid-induced steatosis in L-02 cellsrdquo WorldJournal of Gastroenterology vol 17 no 19 pp 2379ndash2388 2011

[127] S I Berger and R Iyengar ldquoNetwork analyses in systemspharmacologyrdquo Bioinformatics vol 25 no 19 pp 2466ndash24722009

[128] A DW Boran and R Iyengar ldquoSystems pharmacologyrdquoMountSinai Journal of Medicine vol 77 no 4 pp 333ndash344 2010

[129] E Ericson M Gebbia L E Heisler et al ldquoOff-target effects ofpsychoactive drugs revealed by genome-wide assays in yeastrdquoPLoS Genetics vol 4 no 8 Article ID e1000151 2008

[130] Y Wang E Bolton S Dracheva et al ldquoAn overview of thePubChem BioAssay resourcerdquo Nucleic Acids Research vol 38no 1 Article ID gkp965 pp D255ndashD266 2009

[131] Y Wang J Xiao T O Suzek J Zhang J Wang and S HBryant ldquoPubChem a public information system for analyzingbioactivities of small moleculesrdquoNucleic Acids Research vol 37no 2 pp W623ndashW633 2009

[132] PDTD [Potential Drug Target Database] httpwwwdddcaccnpdtd

[133] Z Gao H Li H Zhang et al ldquoPDTD a web-accessible proteindatabase for drug target identificationrdquo BMC Bioinformaticsvol 9 article 104 2008

[134] PDB httpwwwrcsborgpdb[135] H M Berman J Westbrook Z Feng et al ldquoThe protein data

bankrdquo Nucleic Acids Research vol 28 no 1 pp 235ndash242 2000[136] J Drews ldquoDrug discovery a historical perspectiverdquo Science vol

287 no 5460 pp 1960ndash1964 2000[137] B Leader Q J Baca and D E Golan ldquoProtein therapeutics a

summary and pharmacological classificationrdquo Nature ReviewsDrug Discovery vol 7 no 1 pp 21ndash39 2008

[138] A L Hopkins and C R Groom ldquoThe druggable genomerdquoNature Reviews Drug Discovery vol 1 no 9 pp 727ndash730 2002

[139] Q Li T Cheng Y Wang and S H Bryant ldquoPubChem as apublic resource for drug discoveryrdquo Drug Discovery Today vol15 no 23-24 pp 1052ndash1057 2010

[140] Sunset Molecular httpwwwsunsetmolecularcom[141] Welcome to NetScirsquos List of Cheminformatics Databases http

wwwnetsciorgResourcesSoftwareCheminfodatabaseshtml[142] DrugBank httpwwwdrugbankca[143] D S Wishart C Knox A C Guo et al ldquoDrugBank a compre-

hensive resource for in silico drug discovery and explorationrdquoNucleic Acids Research vol 34 pp D668ndash672 2006

[144] B Oh C H Um M K Lee et al ldquoTHINKherb the HerbINformation Knowledge basemdashthe chip content database forherbal medicinerdquo Biochip Journal vol 2 no 4 pp 274ndash2792009

[145] ldquoTraditional Chinese medicine information databaserdquo httptcmcz3nusedusggrouptcm-idtcmid nsasp

[146] X Chen H Zhou Y B Liu et al ldquoDatabase of traditionalChinese medicine and its application to studies of mechanismand to prescription validationrdquo British Journal of Pharmacologyvol 149 no 8 pp 1092ndash1103 2006

[147] Traditional Chinese medicines integrated database httpwwwmegabionetorgtcmid

[148] R Xue Z Fang M Zhang Z Yi C Wen and T Shi ldquoTCMIDtraditional Chinese medicine integrative database for herbmolecular mechanism analysisrdquo Nucleic Acids Research vol 41no 1 pp D1089ndashD1095 2013

[149] U Vetrivel N Subramanian and K Pilla ldquoInPACdb-Indianplant anticancer compounds databaserdquo Bioinformation vol 4no 2 pp 71ndash74 2009 httpwwwinpacdborg



[151] A P Russ and S Lampel ldquoThe druggable genome an updaterdquoDrug Discovery Today vol 10 no 23-24 pp 1607ndash1610 2005

[152] A D W Boran and R Iyengar ldquoSystems approaches topolypharmacology and drug discoveryrdquo Current Opinion inDrug Discovery and Development vol 13 no 3 pp 297ndash3092010

[153] J P Overington B Al-Lazikani and A L Hopkins ldquoHowmanydrug targets are thererdquo Nature Reviews Drug Discovery vol 5no 12 pp 993ndash996 2006

[154] J P A Ioannidis and O A Panagiotou ldquoComparison ofeffect sizes associated with biomarkers reported in highly citedindividual articles and in subsequent meta-analysesrdquo Journal ofthe American Medical Association vol 305 no 21 pp 2200ndash2210 2011

[155] S R Smith ldquoMetabolic syndrome targetsrdquo Current Drug Tar-gets-CNS amp Neurological Disorders vol 3 no 5 pp 431ndash4392004

[156] L Brown ldquoTargets of research in the metabolic syndromerdquoEndocrine Metabolic and Immune Disorders vol 11 no 3 p 1812011

[157] OWitt H E Deubzer T Milde and I Oehme ldquoHDAC familywhat are the cancer relevant targetsrdquo Cancer Letters vol 277no 1 pp 8ndash21 2009

[158] M G Butler ldquoGenetics of hypertension Current statusrdquo TheLebanese Medical Journal vol 58 no 3 pp 175ndash178 2010

[159] R Machado-Vieira G Salvadore N DiazGranados et al ldquoNewtherapeutic targets formooddisordersrdquoTheScientificWorldJour-nal vol 10 pp 713ndash726 2010

[160] C Heim and C B Nemeroff ldquoNeurobiology of posttraumaticstress disorderrdquo CNS Spectrums vol 14 no 1 pp 13ndash24 2009

[161] D H Kim and S M Stahl ldquoAntipsychotic drug developmentrdquoCurrent topics in Behavioral Neurosciences vol 4 pp 123ndash1392010

[162] M Asai N Iwata T Tomita et al ldquoEfficient four-drug cocktailtherapy targeting amyloid-120573 peptide for Alzheimerrsquos diseaserdquoJournal of Neuroscience Research vol 88 no 16 pp 3588ndash35972010

[163] C Ruiz-Romero and F J Blanco ldquoThe role of proteomics inosteoarthritis pathogenesis researchrdquoCurrent Drug Targets vol10 no 6 pp 543ndash556 2009

[164] P L Earl C Cotter B Moss et al ldquoDesign and evaluation ofmulti-gene multi-clade HIV-1 MVA vaccinesrdquo Vaccine vol 27no 42 pp 5885ndash5895 2009

[165] D Borsook L Becerra and R Hargreaves ldquoBiomarkers forchronic pain and analgesia Part 1 the need reality challengesand solutionsrdquo Discovery Medicine vol 11 no 58 pp 197ndash2072011

[166] J A Saonere ldquoAntisense therapy a magic bullet for the treat-ment of various diseases present and future prospectsrdquo Journalof Medical Genetics and Genomics vol 3 no 5 pp 77ndash83 2011

[167] ldquoTransient ischemic attackrdquo httpmedical-dictionarythefree-dictionarycomTransient+ischaemic+episode

[168] V E OrsquoCollins M R Macleod G A Donnan L L HorkyB H van der Worp and D W Howells ldquo1026 Experimentaltreatments in acute strokerdquo Annals of Neurology vol 59 no 3pp 467ndash477 2006

[169] P M DrsquoOnofrio M Thayapararajah M D Lysko et al ldquoGenetherapy for traumatic central nervous system injury and strokeusing an engineered zinc finger protein that upregulates VEGF-Ardquo Journal of Neurotrauma vol 28 no 9 pp 1863ndash1879 2011

[170] H B van der Worp E S Sena G A Donnan D W Howellsand M R Macleod ldquoHypothermia in animal models of acuteischaemic stroke a systematic review andmeta-analysisrdquo Brainvol 130 no 12 pp 3063ndash3074 2007

[171] T Miyazawa A Tamura S Fukui and K A Hossmann ldquoEffectof mild hypothermia on focal cerebral ischemia Review ofexperimental studiesrdquo Neurological Research vol 25 no 5 pp457ndash464 2003

[172] H M den Hertog H B van der Worp M C Tseng and D WDippel ldquoCooling therapy for acute strokerdquo Cochrane Databaseof Systematic Reviews no 1 Article ID CD001247 2009

[173] L Xie J Li L Xie and P E Bourne ldquoDrug discovery usingchemical systems biology identification of the protein-ligandbinding network to explain the side effects of CETP inhibitorsrdquoPLoS Computational Biology vol 5 no 5 Article ID e10003872009

[174] H Zhou C S Beevers and SHuang ldquoThe targets of curcuminrdquoCurrent Drug Targets vol 12 no 3 pp 332ndash347 2011

[175] SMWilhelm L Adnane P Newell A Villanueva J M LlovetandM Lynch ldquoPreclinical overview of sorafenib a multikinaseinhibitor that targets both Raf and VEGF and PDGF receptortyrosine kinase signalingrdquo Molecular Cancer Therapeutics vol7 no 10 pp 3129ndash3140 2008

[176] J Mestres E Gregori-Puigjane S Valverde and R V SoleldquoData completenessmdashthe achilles heel of drug-target networksrdquoNature Biotechnology vol 26 no 9 pp 983ndash984 2008

[177] ldquoNew drug failure rates rising in Phase II and III clinical tri-alsrdquo httpwwwmedcitynewscom201106new-drug-failure-rates-rising-in-phase-ii-and-iii-clinical-trials

[178] A Birmingham E M Anderson A Reynolds et al ldquo3rsquoUTRseed matches but not overall identity are associated with RNAioff-targetsrdquo Nature Methods vol 3 no 3 pp 199ndash204 2006

[179] S M Drawz and R A Bonomo ldquoThree decades of 120573-lactamaseinhibitorsrdquoClinicalMicrobiology Reviews vol 23 no 1 pp 160ndash201 2010

[180] ldquoWarning over threat posed by new superbugs resistant to ldquolastresortrdquo antibioticsrdquo httpteotwawkiwsp=948

[181] ldquoAre you taking antibiotics without knowing itrdquo httpwwwconsumer-healthcomservicescons take66php


[183] F Hormozdiari P Berenbrink N Przulj and S C SahinalpldquoNot all scale-free networks are born equal the role of the seedgraph in PPI network evolutionrdquo PLoS Computational Biologyvol 3 no 7 article e118 2007

[184] K A Forde and K R Reddy ldquoHepatitis C Virus Infection andImmunomodulatoryTherapiesrdquo Clinics in Liver Disease vol 13no 3 pp 391ndash401 2009

[185] V G Athyros K Tziomalos A Karagiannis and D P Mikhai-lidis ldquoDyslipidaemia of obesity metabolic syndrome and type 2diabetes mellitus the case for residual risk reduction after statintreatmentrdquo The Open Cardiovascular Medicine Journal vol 5pp 24ndash34 2011

[186] P F Wu Z Zhang F Wang and J G Chen ldquoNaturalcompounds from traditional medicinal herbs in the treatmentof cerebral ischemiareperfusion injuryrdquo Acta PharmacologicaSinica vol 31 no 12 pp 1523ndash1531 2010

[187] NIH news release httpwwwnihgovnewsprjun2000nhgri-26htm


[188] R Galeazzi ldquoMolecular dynamics as a tool in rational drugdesign current status and some major applicationsrdquo CurrentComputer-Aided Drug Design vol 5 no 4 pp 225ndash240 2009

[189] M de Vivo ldquoBridging quantummechanics and structure-baseddrug designrdquo Frontiers in Bioscience vol 16 no 5 pp 1619ndash16332011

[190] K Raha M B Peters B Wang et al ldquoThe role of quantummechanics in structure-based drug designrdquo Drug DiscoveryToday vol 12 no 17-18 pp 725ndash731 2007

[191] S F Zhou Z W Zhou C G Li et al ldquoIdentification of drugsthat interact with herbs in drug developmentrdquo Drug DiscoveryToday vol 12 no 15-16 pp 664ndash673 2007

[192] G M Cragg and D J Newman ldquoInternational collaborationin drug discovery and development from natural sourcesrdquo Pureand Applied Chemistry vol 77 no 11 pp 1923ndash1942 2005

[193] ldquoGene expression profilingmdashChinese medicine functionalgenomics research Reflecrdquo httpwwwbiosinoorgnews-200220020302031507htm

[194] J W A van der Hoorn J W Jukema L M Havekes et al ldquoThedual PPAR120572120574 agonist tesaglitazar blocks progression of pre-existing atherosclerosis in APOElowast3LeidenCETP transgenicmicerdquo British Journal of Pharmacology vol 156 no 7 pp 1067ndash1075 2009

[195] R Balazs J Vernon and J Hardy ldquoEpigenetic mechanisms inAlzheimerrsquos disease progress but much to dordquo Neurobiology ofAging vol 32 no 7 pp 1181ndash1187 2011

[196] P Hollingworth D Harold R Sims et al ldquoCommon variantsat ABCA7 MS4A6AMS4A4E EPHA1 CD33 and CD2AP areassociated with Alzheimerrsquos diseaserdquo Nature Genetics vol 43no 5 pp 429ndash436 2011

[197] A C Naj G Jun G W Beecham et al ldquoCommon variantsat MS4A4MS4A6E CD2AP CD33 and EPHA1 are associatedwith late-onsetAlzheimerrsquos diseaserdquoNatureGenetics vol 43 no5 pp 436ndash441 2011

[198] A R Desilets J J Gickas and K C Dunican ldquoRole ofhuperzine A in the treatment of alzheimerrsquos diseaserdquoTheAnnalsof Pharmacotherapy vol 43 no 3 pp 514ndash518 2009

[199] J Li HMWu R L ZhouG J Liu andB RDong ldquoHuperzineA for Alzheimerrsquos diseaserdquo Cochrane Database of SystematicReviews no 2 Article ID CD005592 2008

[200] J T Little S Walsh and P S Aisen ldquoAn update on huperzineA as a treatment for Alzheimerrsquos diseaserdquo Expert Opinion onInvestigational Drugs vol 17 no 2 pp 209ndash215 2008

[201] H Y Zhang C Y Zheng H Yan et al ldquoPotential therapeutictargets of huperzine A for Alzheimerrsquos disease and vasculardementiardquo Chemico-Biological Interactions vol 175 no 1ndash3 pp396ndash402 2008

[202] H Y Zhang H Yan and X C Tang ldquoNon-cholinergic effectsof huperzine A beyond inhibition of acetylcholinesteraserdquoCellular and Molecular Neurobiology vol 28 no 2 pp 173ndash1832008

[203] ldquoOne thousand kinds of animals and plants Genome Pro-jectrdquo (Chinese) httpnewssciencenetcnhtmlnews20105232132shtm

[204] ldquoChina has successfully developed the worldrsquos first medici-nal plant genome framework maprdquo (Chinese) httpnewssci-encenetcnhtmlnews20106233548shtm

[205] B Liu HWang Z Du G Li andH Ye ldquoMetabolic engineeringof artemisinin biosynthesis in Artemisia annua Lrdquo Plant CellReports vol 30 no 5 pp 689ndash694 2011

[206] C Liu Y Zhao and Y Wang ldquoArtemisinin current state andperspectives for biotechnological production of an antimalarialdrugrdquoAppliedMicrobiology and Biotechnology vol 72 no 1 pp11ndash20 2006

[207] D K Ro E M Paradise M Quellet et al ldquoProduction ofthe antimalarial drug precursor artemisinic acid in engineeredyeastrdquo Nature vol 440 no 7086 pp 940ndash943 2006

[208] J R Lenihan H Tsuruta D Diola N S Renninger and RRegentin ldquoDeveloping an industrial artemisinic acid fermen-tation process to support the cost-effective production of anti-malarial artemisinin-based combination therapiesrdquo Biotechnol-ogy Progress vol 24 no 5 pp 1026ndash1032 2008

[209] The human genome project httpwwwessortmentcomhuman-genome-project-59573html

[210] G M Cragg and D J Newman ldquoNature a vital source of leadsfor anticancer drug developmentrdquo Phytochemistry Reviews vol8 no 2 pp 313ndash331 2009

[211] ldquoMice men share 99 percent of genesrdquo httpeditioncnncom2002TECHscience1204coolsccoolscmousegenome

[212] B J Culliton ldquoThe humanized flyrdquo wwwbarbaracullitoncomhumanized flypdf

[213] C Napoli C Lemieux and R Jorgensen ldquoIntroduction of a chi-meric chalcone synthase gene into petunia results in reversibleco-suppression of homologous genes in transrdquo The Plant Cellvol 2 no 4 pp 279ndash289 1990

[214] Z Zhao Z Liang K Chan et al ldquoA unique issue in thestandardization of Chinese materia medica processingrdquo PlantaMedica vol 76 no 17 pp 1975ndash1986 2010

[215] F Liao ldquoDiscovery of artemisinin (Qinghaosu)rdquoMolecules vol14 no 12 pp 5362ndash5366 2009

[216] ldquoProcess of artemisinin discoveryrdquo httpblogsciencenetcnhomephpmod=spaceampuid=396469ampdo=blogampid=365064

[217] ldquoEcological ethicsrdquo httpstatsoecdorgglossarydetailaspID=716

[218] J S Singh ldquoThe biodiversity crisis a multifaceted reviewrdquoCurrent Science vol 82 pp 638ndash647 2002

[219] Please donrsquot ask us to carry these herbs httpwwwfron-tiercoopcomlearnherbsphp

[220] ldquoProtection of endangered CHMrdquo (Chinese) httpwwwzhong-yaonetyscc20080290460html

[221] ldquoChinese herbal medicinal decodingrdquo (Chinese) httpitoyk-softcompost2505

[222] L Y Li B Z Ciren D Zhan and Y F Wei ldquoComprehensiveutilization and development of traditional Tibetan medicine inChinardquoChina Journal of ChineseMateriaMedica vol 26 no 12pp 808ndash810 2001 (Chinese)

[223] L Huang B Yang M Wang and G Fu ldquoAn approach to someproblems on utilization of medicinal plant resource in ChinardquoChina Journal of Chinese Materia Medica vol 24 no 2 pp 70ndash73 1999 (Chinese)

[224] ldquoEndangered wild plants in Chinese Herbal Medicinerdquo(Chinese) httpwwwzhong-yaonetzysczy200803107540html

[225] H Azaizeh B Saad K Khalil and O Said ldquoThe state of the artof traditional Arab herbal medicine in the Eastern region of theMediterranean a reviewrdquo Evidence-based Complementary andAlternative Medicine vol 3 no 2 pp 229ndash235 2006

[226] P Marson and G Pasero ldquoThe Italian contributions to thehistory of salicylatesrdquo Reumatismo vol 58 no 1 pp 66ndash752006 (Italian)


[227] J G Mahdi A J Mahdi A J Mahdi and I D BowenldquoThe historical analysis of aspirin discovery its relation to thewillow tree and antiproliferative and anticancer potentialrdquo CellProliferation vol 39 no 2 pp 147ndash155 2006

[228] K C Zhao and Z Y Song ldquoPharmacokinetics of dihydroqing-haosu in human volunteers and comparison with qinghaosurdquoActa Pharmaceutica Sinica vol 28 no 5 pp 342ndash346 1993(Chinese)

[229] Q G Li J O Peggins L L Fleckenstein K Masonic M HHeiffer and T G Brewer ldquoThe pharmacokinetics and bioavail-ability of dihydroartemisinin arteether artemether artesunicacid and artelinic acid in ratsrdquo The Journal of Pharmacy andPharmacology vol 50 no 2 pp 173ndash182 1998

[230] ldquoProgress in standardized planting of Chinese herbalmedicinesrdquo (Chinese) httpwwwmed66comnew56a294a-2010201047qiji112120shtml

[231] ldquoMedicinal plantsrdquo (Chinese) wwwhm160cn1211211108htm[232] B Zhang Y Peng Z Zhang et al ldquoGAP production of TCM

herbs in Chinardquo Planta Medica vol 76 no 17 pp 1948ndash19552010

[233] H Heuberger R Bauer F Friedl et al ldquoCultivation and breed-ing of Chinese medicinal plants in Germanyrdquo Planta Medicavol 76 no 17 pp 1956ndash1962 2010

[234] L Zhang F Jing F Li et al ldquoDevelopment of transgenicArtemisia annua (Chinese worm-wood) plants with an en-hanced content of artemisinin an effective anti-malarial drugby hairpin-RNA-mediated gene silencingrdquo Biotechnology andApplied Biochemistry vol 52 no 3 pp 199ndash207 2009

[235] A Baldi and V K Dixit ldquoYield enhancement strategies forartemisinin production by suspension cultures of Artemisiaannuardquo Bioresource Technology vol 99 no 11 pp 4609ndash46142008

[236] J D Newman J Marshall M Chang et al ldquoHigh-level produc-tion of amorpha-411-diene in a two-phase partitioning bioreac-tor of metabolically engineered Escherichia colirdquo Biotechnologyand Bioengineering vol 95 no 4 pp 684ndash691 2006

[237] J H Wang W Lia Y Sha Y Tezuka S Kadota and X LildquoTriterpenoid saponins from leaves and stems of Panax quin-quefolium Lrdquo Journal of Asian Natural Products Research vol 3no 2 pp 123ndash130 2001

[238] J Chen R Zhao Y M Zeng et al ldquoThree new triterpenoidsaponins from the leaves and stems of Panax quinquefoliumrdquoJournal of AsianNatural Products Research vol 11 no 3 pp 195ndash201 2009

[239] A Gurib-Fakim ldquoMedicinal plants traditions of yesterday anddrugs of tomorrowrdquo Molecular Aspects of Medicine vol 27 no1 pp 1ndash93 2006

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Drug discovery

Automated separation techniques

Metabonomics

Bioinformatics

Proteomics

Biochip Genomics

System biologyTranscriptomics

Transgenic and RNAi technology

Computer-aideddrug design

High-throughput andhigh content screening

Figure 1 An array of technology platforms driving drug discovery

market in 1996 [3 4] Despite the protracted time courseof development only one or two in ten thousand of suchchemical compounds have proven to be clinically efficaciousand safe for approval by regulatory agencies In fact abouthalf of all drug candidates fail in the late stages of clinicaltrials Furthermore soon after their approval some newdrugs have to be withdrawn from the market due to severeside effects and clinical risks that are not detected in Phase IIItrials For example Vioxx (rofecoxib) which was launched in1999 was withdrawn in 2004 due to an increased risk of heartattack in users As a result the drug only existed in themarketfor 5 years and this was compounded by the huge sum (US$485 billion) of compensation involved in lawsuits [5] Giventhat the development of synthetic chemicals for therapeuticuse is by and large a random process that might result inserendipitous discoverymany pharmaceutical companies arenow focused on the development of plant-derived drugs

Complementary and alternative medicine therapies(CAMTs) which have been gaining popularity throughoutthe world are classified into drug-based CAMT and non-drug-based CAMT [6] Among various drug-based CAMTsmedicines (more than 80) commonly practiced are herbsof plant origin Human beings have evolved from the simpleherbivorous animals to omnivorous ones As such we noweat both plants and meats A wealth of experience on theapplication of herbalplant materials used in promotinghealth has accumulated over centuries and the informationis readily available for modern scientific research on drugdiscovery The earliest evidence of human use of plants forhealing can date back to the Neanderthal period [7] As aconsequence plant-derived herbs may interact favorablywith the human body and hence produce beneficial effectsin terms of health promotion Interestingly it has beenobserved that nonhuman vertebrates will eat some typesof plants for self-medication under disease conditions[8ndash10] Not surprisingly the observations of eating behaviorand serendipitous events in wild animals have led to thediscovery of herbsplants with therapeutic potential Inthis regard the study on self-medication in animals mayoffer a novel approach to drug discovery for humans For

instance novel antimalarial compounds were isolated fromthe leaves of Trichilia rubescens based on a behavioral surveyof chimpanzees from a natural population in Uganda [2]

In two recent articles we have discussed a total of tenapproaches in new drug discovery as well as the researchand development of traditional herbal medicine ldquo(THM)rdquo inrelation to modern drug discovery [11 12] While advancesin new technologies have revolutionized the process of drugdiscovery the successful development of a novel therapeuticagent is critically dependent on whether the process paysrespect to nature adopts new approachesconcepts andinvolves the studies on ADMET (ie absorption distribu-tion metabolism excretion and toxicity) in the early stagesof drug discovery Furthermore the safe and optimal useof herbal medicines requires a full understanding of theirADME and herb-syntheticherb-herb interaction profiles[13ndash16] In this paper we focused on the discovery of chem-icals for therapeutic usage from herbal medicines especiallyTHMwith an extremely valuable rich lengthy and extensivepractical history

2 Current Approaches of Drug Discovery fromHerbal Medicine

Today approximately 80 of antimicrobial cardiovascularimmunosuppressive and anticancer drugs are of plant origintheir sales exceeded US$ 65 billion in 2003 [17] It is widelyaccepted that more than 80 of drug substances are eitherdirectly derived from natural products or developed froma natural compound [18] And in fact around 50 ofpharmaceuticals are derived from compounds first identifiedor isolated from herbsplants including organisms animalsand insects as active ingredients [19] Drug discovery fromherbsmay be divided into three stages namely predrug stagequasidrug stage and full-drug stage They are described indetail in Figure 2

21 Predrug Stage It has been estimated that approximately420000 plant species exist on earth but for most of these













Marketed drug


Folk medicines

Wild animal eating

behavior



Clinic trial


culture

Herb or preparation


Hybrid

molecules

Extracts

medicine system


Botanical medicine

Foodstuffs







salts and so forth


Singlecompound


modification

Preclinicstudy

Full-drugstage

Herbal-to-synthetic

Herbal-to-herbal



















Herbal extracts

Dry herb

New techniques



Water extraction

Fresh herb








Steam distillation

Enzyme method




















Artemisinin






Ester derivatives

Ether derivatives

Alkyl ether

Aromatic ether

O-aminoether


Figure 4








Oral andinjectable

Oral andsuppository

Injectable


H

H

H

OO

O

O

O

O

O

OH

H

H

H

OO

O

O

O

H

H

H

OO

O

O

O

H

H

H

OO

O

O

O

O

O

OO

H

H

H

OH

O O

X

O O

X

O OR

O

O

O O

O




NP17 NP18


Predrug

Quasidrug



Insoluble in water

Insoluble in oil




Full-drug




O

O

OO

H

H

N

SO O

O

O

H

H

N

S


OO

120573-arteether






Bicyclol

O

OO

OO

O

Br

Br OO

OO

O

OO

O

O

O

O

O

O

O

O

O

O

O

O

H

PredrugQuasidrug



Full-drug










4-Hydroxy-4







Hepatomegaly



IG

IG

Bicyclol

Bifendate

Extracts of

FSC

Plasma turbidity












Safety Efficacy

Safety Efficacy

1

2

3

4







Synthetics

Toxicology









DrugBank

BioAssayPubChem



(WOMBAT)


database (TCMID)



(InPACdb)













Pathogenomics

Bioinformatics

Transcriptomics


Proteomics

Pharmacogenomics

Functional genomics


Cancer genomics

Toxicogenomics

Ecotoxicogenomics

Nutrigenomics

Interactomics

Epigenomics


Are

peo

ple g

enes

Structural genomics


PGE





























Save the endangered

herbal medicine


species


plants

Control the usage

Prohibits the usage

Full use

Cell culture




ingredients



















Acknowledgments


References





























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























Marketed drug


Folk medicines

Wild animal eating

behavior



Clinic trial


culture

Herb or preparation


Hybrid

molecules

Extracts

medicine system


Botanical medicine

Foodstuffs







salts and so forth


Singlecompound


modification

Preclinicstudy

Full-drugstage

Herbal-to-synthetic

Herbal-to-herbal



















Herbal extracts

Dry herb

New techniques



Water extraction

Fresh herb








Steam distillation

Enzyme method




















Artemisinin






Ester derivatives

Ether derivatives

Alkyl ether

Aromatic ether

O-aminoether


Figure 4








Oral andinjectable

Oral andsuppository

Injectable


H

H

H

OO

O

O

O

O

O

OH

H

H

H

OO

O

O

O

H

H

H

OO

O

O

O

H

H

H

OO

O

O

O

O

O

OO

H

H

H

OH

O O

X

O O

X

O OR

O

O

O O

O




NP17 NP18


Predrug

Quasidrug



Insoluble in water

Insoluble in oil




Full-drug




O

O

OO

H

H

N

SO O

O

O

H

H

N

S


OO

120573-arteether






Bicyclol

O

OO

OO

O

Br

Br OO

OO

O

OO

O

O

O

O

O

O

O

O

O

O

O

O

H

PredrugQuasidrug



Full-drug










4-Hydroxy-4







Hepatomegaly



IG

IG

Bicyclol

Bifendate

Extracts of

FSC

Plasma turbidity












Safety Efficacy

Safety Efficacy

1

2

3

4







Synthetics

Toxicology









DrugBank

BioAssayPubChem



(WOMBAT)


database (TCMID)



(InPACdb)













Pathogenomics

Bioinformatics

Transcriptomics


Proteomics

Pharmacogenomics

Functional genomics


Cancer genomics

Toxicogenomics

Ecotoxicogenomics

Nutrigenomics

Interactomics

Epigenomics


Are

peo

ple g

enes

Structural genomics


PGE





























Save the endangered

herbal medicine


species


plants

Control the usage

Prohibits the usage

Full use

Cell culture




ingredients



















Acknowledgments


References





























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























Herbal extracts

Dry herb

New techniques



Water extraction

Fresh herb








Steam distillation

Enzyme method




















Artemisinin






Ester derivatives

Ether derivatives

Alkyl ether

Aromatic ether

O-aminoether


Figure 4








Oral andinjectable

Oral andsuppository

Injectable


H

H

H

OO

O

O

O

O

O

OH

H

H

H

OO

O

O

O

H

H

H

OO

O

O

O

H

H

H

OO

O

O

O

O

O

OO

H

H

H

OH

O O

X

O O

X

O OR

O

O

O O

O




NP17 NP18


Predrug

Quasidrug



Insoluble in water

Insoluble in oil




Full-drug




O

O

OO

H

H

N

SO O

O

O

H

H

N

S


OO

120573-arteether






Bicyclol

O

OO

OO

O

Br

Br OO

OO

O

OO

O

O

O

O

O

O

O

O

O

O

O

O

H

PredrugQuasidrug



Full-drug










4-Hydroxy-4







Hepatomegaly



IG

IG

Bicyclol

Bifendate

Extracts of

FSC

Plasma turbidity












Safety Efficacy

Safety Efficacy

1

2

3

4







Synthetics

Toxicology









DrugBank

BioAssayPubChem



(WOMBAT)


database (TCMID)



(InPACdb)













Pathogenomics

Bioinformatics

Transcriptomics


Proteomics

Pharmacogenomics

Functional genomics


Cancer genomics

Toxicogenomics

Ecotoxicogenomics

Nutrigenomics

Interactomics

Epigenomics


Are

peo

ple g

enes

Structural genomics


PGE





























Save the endangered

herbal medicine


species


plants

Control the usage

Prohibits the usage

Full use

Cell culture




ingredients



















Acknowledgments


References





























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























Artemisinin






Ester derivatives

Ether derivatives

Alkyl ether

Aromatic ether

O-aminoether


Figure 4








Oral andinjectable

Oral andsuppository

Injectable


H

H

H

OO

O

O

O

O

O

OH

H

H

H

OO

O

O

O

H

H

H

OO

O

O

O

H

H

H

OO

O

O

O

O

O

OO

H

H

H

OH

O O

X

O O

X

O OR

O

O

O O

O




NP17 NP18


Predrug

Quasidrug



Insoluble in water

Insoluble in oil




Full-drug




O

O

OO

H

H

N

SO O

O

O

H

H

N

S


OO

120573-arteether






Bicyclol

O

OO

OO

O

Br

Br OO

OO

O

OO

O

O

O

O

O

O

O

O

O

O

O

O

H

PredrugQuasidrug



Full-drug










4-Hydroxy-4







Hepatomegaly



IG

IG

Bicyclol

Bifendate

Extracts of

FSC

Plasma turbidity












Safety Efficacy

Safety Efficacy

1

2

3

4







Synthetics

Toxicology









DrugBank

BioAssayPubChem



(WOMBAT)


database (TCMID)



(InPACdb)













Pathogenomics

Bioinformatics

Transcriptomics


Proteomics

Pharmacogenomics

Functional genomics


Cancer genomics

Toxicogenomics

Ecotoxicogenomics

Nutrigenomics

Interactomics

Epigenomics


Are

peo

ple g

enes

Structural genomics


PGE





























Save the endangered

herbal medicine


species


plants

Control the usage

Prohibits the usage

Full use

Cell culture




ingredients



















Acknowledgments


References





























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Oral andinjectable

Oral andsuppository

Injectable


H

H

H

OO

O

O

O

O

O

OH

H

H

H

OO

O

O

O

H

H

H

OO

O

O

O

H

H

H

OO

O

O

O

O

O

OO

H

H

H

OH

O O

X

O O

X

O OR

O

O

O O

O




NP17 NP18


Predrug

Quasidrug



Insoluble in water

Insoluble in oil




Full-drug




O

O

OO

H

H

N

SO O

O

O

H

H

N

S


OO

120573-arteether






Bicyclol

O

OO

OO

O

Br

Br OO

OO

O

OO

O

O

O

O

O

O

O

O

O

O

O

O

H

PredrugQuasidrug



Full-drug










4-Hydroxy-4







Hepatomegaly



IG

IG

Bicyclol

Bifendate

Extracts of

FSC

Plasma turbidity












Safety Efficacy

Safety Efficacy

1

2

3

4







Synthetics

Toxicology









DrugBank

BioAssayPubChem



(WOMBAT)


database (TCMID)



(InPACdb)













Pathogenomics

Bioinformatics

Transcriptomics


Proteomics

Pharmacogenomics

Functional genomics


Cancer genomics

Toxicogenomics

Ecotoxicogenomics

Nutrigenomics

Interactomics

Epigenomics


Are

peo

ple g

enes

Structural genomics


PGE





























Save the endangered

herbal medicine


species


plants

Control the usage

Prohibits the usage

Full use

Cell culture




ingredients



















Acknowledgments


References





























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Bicyclol

O

OO

OO

O

Br

Br OO

OO

O

OO

O

O

O

O

O

O

O

O

O

O

O

O

H

PredrugQuasidrug



Full-drug










4-Hydroxy-4







Hepatomegaly



IG

IG

Bicyclol

Bifendate

Extracts of

FSC

Plasma turbidity












Safety Efficacy

Safety Efficacy

1

2

3

4







Synthetics

Toxicology









DrugBank

BioAssayPubChem



(WOMBAT)


database (TCMID)



(InPACdb)













Pathogenomics

Bioinformatics

Transcriptomics


Proteomics

Pharmacogenomics

Functional genomics


Cancer genomics

Toxicogenomics

Ecotoxicogenomics

Nutrigenomics

Interactomics

Epigenomics


Are

peo

ple g

enes

Structural genomics


PGE





























Save the endangered

herbal medicine


species


plants

Control the usage

Prohibits the usage

Full use

Cell culture




ingredients



















Acknowledgments


References





























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Hepatomegaly



IG

IG

Bicyclol

Bifendate

Extracts of

FSC

Plasma turbidity












Safety Efficacy

Safety Efficacy

1

2

3

4







Synthetics

Toxicology









DrugBank

BioAssayPubChem



(WOMBAT)


database (TCMID)



(InPACdb)













Pathogenomics

Bioinformatics

Transcriptomics


Proteomics

Pharmacogenomics

Functional genomics


Cancer genomics

Toxicogenomics

Ecotoxicogenomics

Nutrigenomics

Interactomics

Epigenomics


Are

peo

ple g

enes

Structural genomics


PGE





























Save the endangered

herbal medicine


species


plants

Control the usage

Prohibits the usage

Full use

Cell culture




ingredients



















Acknowledgments


References





























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Safety Efficacy

Safety Efficacy

1

2

3

4







Synthetics

Toxicology









DrugBank

BioAssayPubChem



(WOMBAT)


database (TCMID)



(InPACdb)













Pathogenomics

Bioinformatics

Transcriptomics


Proteomics

Pharmacogenomics

Functional genomics


Cancer genomics

Toxicogenomics

Ecotoxicogenomics

Nutrigenomics

Interactomics

Epigenomics


Are

peo

ple g

enes

Structural genomics


PGE





























Save the endangered

herbal medicine


species


plants

Control the usage

Prohibits the usage

Full use

Cell culture




ingredients



















Acknowledgments


References





























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















DrugBank

BioAssayPubChem



(WOMBAT)


database (TCMID)



(InPACdb)













Pathogenomics

Bioinformatics

Transcriptomics


Proteomics

Pharmacogenomics

Functional genomics


Cancer genomics

Toxicogenomics

Ecotoxicogenomics

Nutrigenomics

Interactomics

Epigenomics


Are

peo

ple g

enes

Structural genomics


PGE





























Save the endangered

herbal medicine


species


plants

Control the usage

Prohibits the usage

Full use

Cell culture




ingredients



















Acknowledgments


References





























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Pathogenomics

Bioinformatics

Transcriptomics


Proteomics

Pharmacogenomics

Functional genomics


Cancer genomics

Toxicogenomics

Ecotoxicogenomics

Nutrigenomics

Interactomics

Epigenomics


Are

peo

ple g

enes

Structural genomics


PGE





























Save the endangered

herbal medicine


species


plants

Control the usage

Prohibits the usage

Full use

Cell culture




ingredients



















Acknowledgments


References





























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





































Save the endangered

herbal medicine


species


plants

Control the usage

Prohibits the usage

Full use

Cell culture




ingredients



















Acknowledgments


References





























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























Acknowledgments


References





























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of










































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article New Perspectives on How to Discover Drugs ...

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