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Drug Discovery: A Historical PerspectiveJurgen Drews

Driven by chemistry but increasingly guided by pharmacology and theclinical sciences, drug research has contributed more to the progress ofmedicine during the past century than any other scientific factor. Theadvent of molecular biology and, in particular, of genomic sciences ishaving a deep impact on drug discovery. Recombinant proteins andmonoclonal antibodies have greatly enriched our therapeutic armamen-tarium. Genome sciences, combined with bioinformatic tools, allow us todissect the genetic basis of multifactorial diseases and to determine themost suitable points of attack for future medicines, thereby increasing thenumber of treatment options. The dramatic increase in the complexity ofdrug research is enforcing changes in the institutional basis of this inter-disciplinary endeavor. The biotech industry is establishing itself as thediscovery arm of the pharmaceutical industry. In bridging the gap betweenacademia and large pharmaceutical companies, the biotech firms havebeen effective instruments of technology transfer.

The Evolution of Drug DiscoveryAs an interdisciplinary endeavor with anindustrial base, drug research is not mucholder than a century. Drug research, as weknow it today, began its career when chem-istry had reached a degree of maturity thatallowed its principles and methods to beapplied to problems outside of chemistryitself and when pharmacology had becomea well-defined scientific discipline in itsown right (1). By 1870, some of the essen-tial foundations of chemical theory hadbeen laid. Avogadro’s atomic hypothesishad been confirmed and a periodic table ofelements established. Chemistry had devel-oped a theory that allowed it to organize theelements according to their atomic weight andvalence. There was also a theory of acids andbases. In 1865, August Kekule formulated hispioneering theory on the structure of aromaticorganic molecules (2, 3).

This benzene theory gave a decisiveimpulse to research on coal-tar derivatives,particularly dyes. In turn, the evolution ofdye chemistry had a profound influence onmedicine. The selective affinity of dyes forbiological tissues led Paul Ehrlich (Fig. 1),a medical student in the laboratory of theanatomist Wilhelm Waldeyer (between1872 and 1874) at the University of Stras-bourg, to postulate the existence of “che-moreceptors.” Ehrlich later argued that cer-tain chemoreceptors on parasites, microor-ganisms, and cancer cells would be differ-ent from analogous structures in hosttissues, and that these differences could beexploited therapeutically. It was the birth ofchemotherapy, a particular type of drugtherapy, that in the course of the 20th cen-

tury led to unprecedented therapeutic tri-umphs (4 ).

Analytical chemistry, in particular the iso-lation and purification of the active ingredi-ents of medicinal plants, also demonstratedits value for medicine in the 19th century. In1815, F. W. Serturner isolated morphine fromopium extract (5). Papaverin was isolated in1848, but its antispasmodic properties werenot discovered until 1917 (6 ). As active in-gredients from plants became available, manypharmacies addressed the problem of provid-ing standardized preparations of these oftenstill impure drugs.

Coal-tar, an abundant by-product of theindustrialization, contained many of the ar-omatic or aliphatic building blocks thatbecame the toolkit of medicinal chemistryfrom its beginnings to the present (7 ). Fi-nally, pharmacology, which had its roots inthe physiological experiments of FrancoisMagendie and Claude Bernard, claimed itsplace among the medical disciplines. Underthe leadership of Oswald Schmiedeberg, theinstitute of pharmacology at the University ofStrasbourg laid many of the intellectual andexperimental foundations of pharmacologybetween 1871 and 1918 (8). However, noneof the institutions that had supported theseseminal efforts—pharmacies, university lab-oratories, or the chemical companies produc-ing dyes—represented suitable platforms forthe newly emerging drug research that wasdriven by chemistry but increasingly con-trolled by pharmacology and by clinical sci-ences. New institutions to support interdisci-plinary drug research and development had tobe created. They either grew out of pharma-cies or were founded as pharmaceutical divi-sions in chemical or dye companies. A newway of finding, characterizing, and develop-ing medicines led to the formation of a newindustry (9).

The Impact of New Technology onDrug DiscoveryDuring the first half of the 20th century drugresearch was shaped and enriched by severalnew technologies, all of which left their im-print on drug discovery and on therapy. In1938, E. Chain, Howard Florey, and theircollaborators selected penicillin, a metabolitefrom a penicillium mold that could lysestaphylococci, for further study (10). Penicil-lin had been discovered in 1929 by AlexanderFleming (11), and a large number of antibi-otic substances had been described in thescientific literature between 1877 and 1939.Chain and Florey’s choice turned out to bevery fortunate. Because of its efficacy andlack of toxicity, penicillin made the mostcompelling case for antibiotics in general. Itopened the door to a new era in the treatmentof bacterial infections. After the discovery ofpenicillin and subsequently of other antibiot-ics, many drug companies established depart-ments of microbiology and fermentationunits, which added to their technologicalscope. There were only a few large compa-nies that did not participate in the search fornew antibiotics. Some companies, for exam-ple Merck, Sandoz, and Takeda, used theirmicrobiological capabilities to find drugs thatexerted other pharmacological or chemother-apeutic properties: Ivermectin, a superior drugagainst tropical filariosis; lovastatin, a HMGA-Co reductase inhibitor; and the immuno-

International Biomedicine Management Partners,Basel, Switzerland and Orbimed Advisors LLC, NewYork, NY 10017–2023, USA.

Fig. 1. Paul Ehrlich, who was the first to arguethat differences in chemoreceptors betweenspecies may be exploited therapeutically. [Im-age: National Library of Medicine]

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suppressants Cyclosporin A and FK 506 areexamples (12–15). Cyclosporin A was dis-covered as early as 1972 in a screening pro-gram for antimicrobial compounds (14 ).

Biochemistry influenced drug research inmany ways. The dominant concepts intro-duced by biochemistry were those of en-zymes and receptors, which were empiricallyfound to be good drug targets. The descrip-tion and characterization of carboanhydrasein 1933 (16 ) was fortuitously followed by thediscovery that sulfanilamide, the active me-tabolite of the sulfonamide (sulfa drug) Pron-tosil, inhibited this enzyme and that this ef-fect led to an increase in natriuresis and theexcretion of water (17 ). Sulfanilamide gaverise to better carboanhydrase inhibitors suchas acetazolamide and later led to more effec-tive diuretics such as hydrochlorothiazide andfurosemide (18). There are structural geneal-ogies that link sulfanilamide with more ad-vanced sulfonamides like sulfathiazole, withsulfonylureas like tolbutamide, used in thetreatment of type II diabetes mellitus, andwith diuretics that are being used to treatedema, glaucoma, or essential hypertension(Fig. 2).

Structural pathways such as the oneshown in Fig. 2 illustrate the fact that thesequential development of different therapeu-tic areas could well be interpreted as chemi-cal diversification that at first occurred spon-taneously. After serendipitous biologicalfindings had been made, certain prototypicstructures were further derivatized in order toobtain compounds with improved or altogeth-er novel effects.

The idea of a receptor as a selective bind-

ing site for chemotherapeutic agents, firstproposed by Paul Ehrlich, has already beenmentioned. A more functional concept inwhich the receptor serves as a “switch” thatreceives and generates specific signals andcan be either blocked by antagonists or turnedon by agonists was introduced into pharma-cology by J. N. Langley in 1905 (19). Acrucial further step in this direction was takenby R. P. Ahlquist in his seminal paper onadrenotropic receptors, in which he proposesthe existence of two types of adrenergic re-ceptors (20). The pharmacological character-ization of receptors in almost all organs, in-cluding the brain, provided the basis for alarge number of very diverse drugs: b-block-ers (21); b-agonists (22); benzodiazepines,which enhance the effects of g-aminobutyricacid and chloride flux by way of the benzo-diazepine receptor (23); and monoclonal an-tibodies, which block receptors of growth ordifferentiation factors on tumor cells (24 ).

A comprehensive analysis of the drug tar-gets underlying current drug therapy under-taken in 1996 showed that present-day ther-apy addresses only about 500 molecular targets.According to the analysis, cell membranereceptors, largely heterotrimeric GTP-bind-ing protein (G protein)–coupled receptors,constitute the largest subgroup with 45% ofall targets, and enzymes account for 28% ofall current drug targets (Fig. 3) (25, 26).

The Influence of Molecular Biology onDrug DiscoveryChemistry, pharmacology, microbiology,and biochemistry helped shape the courseof drug discovery and bring it to a level

where new drugs are no longer generatedsolely by the imagination of chemists butresult from a dialogue between biologistsand chemists. This dialogue, centered on bio-chemical mechanisms of action, stems fromthe understanding of biological structure andfunction and gives rise to the creation ofnovel chemical structures. Molecular biologyhas exerted a profound influence on drugdiscovery, allowing the concept of geneticinformation to be dealt with in very concretebiochemical and chemical terms. At first,however, the influence of molecular biologyappeared to be restricted to cloning and ex-pressing genes that encode therapeuticallyuseful proteins.

The total number of protein drugs,largely recombinant proteins and monoclo-nal antibodies that are often referred to as“biotech” drugs, currently amounts to 59(27 ). Recombinant proteins have becomeimportant additions to the therapeutic ar-mamentarium. After some delay, monoclo-nal antibodies, a specialized form of recom-binant protein, arrived on the scene (28). In1998, biotech products, most of them re-combinant proteins and monoclonal anti-bodies, accounted for 15 out of 57 drugsintroduced worldwide (26.3%). Among the50 leading research-based companies, thecorresponding figures were 7 out of 40(17.5%) (29). The human genome contains12,000 to 14,000 genes encoding secretedproteins. Even if only 1 or 2% of theseproteins were to qualify as drugs, therewould be between 120 and 280 novel ther-apeutic proteins, most of which still remainto be discovered and developed. This figure

Fig. 2. Sons of sulfanilamide.A schematic representationof drugs that originated fromsulfanilamide. A single chemi-cal motif gave rise to antibi-otics, hypoglycemic agents,diuretics, and antihyperten-sive drugs.

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does not, of course, include monoclonalantibodies, which today are produced inthree different ways. They can be generatedas mouse antibodies that are subsequently“humanized” by recombination with humanantibody genes (30 –32). Alternatively, andperhaps preferably, human antibodies canbe directly raised in nude mice grafted withhuman immune cells (33). Finally, antibod-ies can also be made by phage displaytechniques. Huge libraries of human anti-body genes in phages allow the productionand subsequent optimization of a wide ar-ray of antibodies (34 –36 ). In fact, anti-bodies may be more attractive from atherapeutic point of view than recombi-nant cytokines or chemokines because theycan be targeted to very specific struc-tures with almost “surgical” precision,whereas many cytokines have evolved asproteins with redundant, or pleiotropic, ac-tions. Given the therapeutic success ofthe interferons, tissue plasminogen activa-tor, erythropoietin, granulocyte-macrophagecolony-stimulating factor, Herceptin, Ritux-imab, and many others, protein drugs arelikely to make many additional therapeuticcontributions.

However, the main promise of molecu-lar biology for drug discovery lies in thepotential to understand disease processes atthe molecular (genetic) level and to deter-mine the optimal molecular targets for drugintervention. As mentioned, current drugtherapy is based on less than 500 moleculartargets. Early work by the British geneticistSewall Wright indicated that the number ofgenes contributing to multifactorial traitsmay not be very high (37 ). Current esti-mates based on Wright’s work and morerecent studies on hypertension and diabetesmellitus in inbred strains of rats suggestthis number to be between 5 and 10 (38,39). If we count the nosological entitiesthat can be classified as multifactorial dis-eases and include only those that pose amajor medical problem in the industrialworld, on account of their prevalence andseverity, we arrive at a figure between 100and 150. [In fact, the repertoire of diseases

targeted by large pharmaceutical compa-nies at the end of the 20th century is con-siderably smaller (40).] If one accepts thelarger figure of 10 as representing the cor-rect average of the number of the genes thatcontribute to a multifactorial disease, thenthe total number of “disease” genes rele-vant from an industrial point of view maybe 1000. Not every “disease gene” may initself be a feasible target. However, itsfunction will likely be linked to that ofother proteins in physiological or patho-physiological circuits. Assuming that thenumber of such “linked” proteins that con-stitute suitable targets for drug interventionis between 5 and 10 per disease gene, weconcluded that the number of potential drugtargets may lie between 5,000 and 10,000(25). In other words, there are at least 10times as many molecular targets that can beexploited for future drug therapy than arebeing used today.

Target Identification and ValidationThe advent of genomic sciences, rapidDNA sequencing, combinatorial chemistry,cell-based assays, and automated high-throughput screening (HTS) has led to a“new” concept of drug discovery. In thisnew concept, the critical discourse betweenchemists and biologists and the quality ofscientific reasoning are sometimes replacedby the magic of large numbers. Large num-bers of hypothetical targets are incorporat-ed into in vitro or cell-based assays andexposed to large numbers of compoundsrepresenting numerous variations on a fewchemical themes or, more recently, fewervariations on a greater number of themes inhigh-throughput configurations. It was hopedthat this experimental design would be suit-able to identify many substances, whichcan modify the targets in question. Manysuch “hits”— compounds that elicit a posi-tive response in a particular assay—wouldthen give rise to more leads, i.e., com-pounds that continue to show the initialpositive response in more complex models(cells, animals) in a dose-dependent man-ner. Eventually, the number of compounds

also would increase. Based on my experi-ence at Hoffmann–La Roche and informa-tion provided from other sources (41), thenumber of data points generated by largescreening programs at a pharmaceuticalcompany amounted to roughly 200,000 atthe beginning of the 1990s. Data points arescreening results describing the effect ofone compound at one concentration in aparticular test. This figure rose to 5 to 6million at the middle of the decade and ispresently approaching or even passing the50-million mark. So far, this several hun-dredfold increase in the number of raw datahas not yet resulted in a commensurateincrease in research productivity. As mea-sured by the number of new compoundsentering the market place, the top 50 com-panies of the pharmaceutical industry col-lectively have not improved their produc-tivity during the 1990s (42, 43). There is ofcourse the possibility that the average num-ber of compounds committed to develop-ment has increased in the last few years. Inthis case, we would see a greater number oforiginal new chemical entities entering theworld markets within the next decade.

It is difficult to judge the “success” ofthe new paradigm of drug discovery on thebasis of published data. Some pharmaceu-tical companies have acknowledged thatHTS has resulted in a large number of“hits” (44 )—an impression that is corrob-orated by a number of recent publications(Fig. 4) (45– 47 ). However, some industryleaders have expressed disappointment thatvery few leads and development com-pounds, if any, can be credited to the newdrug discovery paradigm (44 ). On the onehand, the meager results may be due to therelatively short period during which thenew drug discovery paradigm has been se-riously implemented. On the other hand,the lack of meaningful results may indicatethat the system has not yet been optimized.What might have gone wrong during thisinitial phase?

Two reasons come to mind, one relatingto biology, the other to chemistry. The factthat “targets” can be hypothetically associat-ed with certain diseases—e.g., leptin or theleptin receptor with obesity (48), the lowdensity lipoprotein receptor with atheroscle-rosis (49), complement receptors with in-flammation (50), or interleukin-4 (IL-4) withallergic diseases (51)—does not mean thatthey represent suitable intervention levels fornew drugs. They need validation, a stepwiseprocess in which the role of a hypotheticaltarget in relation to a disease phenotype isunderstood. There are several levels of targetvalidation: The “credibility” of a target de-pends on the complexity and disease rele-vance of the model in which the target istested. Reproducible and dose-dependent

Fig. 3. Molecular targets of drugtherapy. Classification accordingto biochemical criteria. Based ona modern standard work of phar-macology, the molecular targetsof all known drugs that havebeen characterized as safe andeffective have been collectedand listed according to their bio-chemical nature (62).

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phenotypic changes in isolated cells elicitedby a compound that modifies the target con-stitute the lowest level of validation. If phe-notypic changes can reproducibly be inducedin an animal model that represents at leastsome disease-relevant mechanisms, the de-gree of validation is higher. The credibility ofa target grows with the number of relevantanimal models in which target modificationslead to the desired phenotypic changes. Ofcourse, the highest degree of validation lies indemonstrating that the modification of a tar-get, e.g., the blocking of a receptor or theinhibition of an enzyme, leads to the reversalof disease symptoms in a clinical situation.Screening tests are questions directed at acompound: What is the efficacy, potency, ortoxicity of a substance in a given situation?Inappropriate questions will lead to meaning-less answers, and this is what usually happensin screening programs that are based on non-validated or poorly validated targets.

The genetic definition and functionalanalysis of several thousand drug targets willinevitably include the description of the var-ious alleles of a given target found in differ-ent human populations. These isogenes arethe most likely cause of variations in drugresponses. There are a few striking examplesin which polymorphisms in target genes (theb2 adrenoceptor for albuterol or the CETPprotein for pravastatin) influence drug re-sponses (52, 53). Therefore, the selection ofdrug targets will also have to rely on epide-miological data. Obviously, economic factorswill compel the use of such data not only askeys to “individualized therapy” but—per-haps more importantly—to identify those tar-gets that allow for the broadest coverage inthe treatment of a particular disease.

Combinatorial Chemistry andHigh-Throughput ScreeningMost recent attempts toward the design of com-binatorial libraries have been driven by theintent to generate a high degree of structuraldiversity within a library. It is, however, by nomeans certain to what extent molecular diver-sity as viewed by chemists and as calculated bystructural descriptors resembles diversity as“seen” by a biological target molecule. Dixonand Villar (54) have shown that a protein canbind a set of structurally diverse molecules withvery similar affinities in the nanomolar range,whereas a number of analogs closely related toone of the good binders display only weakaffinities (.2.5 mM). The design and samplingof compound libraries should, therefore, beguided not only by structural descriptors, butalso by descriptors of biological activity. Thiscan be achieved by screening all compounds ina library against a panel of functionally dissim-ilar proteins and determining the binding affin-ity of each compound for each protein. The setof binding affinities for a given compound is

termed its affinity fingerprint. The similarity ofaffinity fingerprints has been shown to correlatewith the biological activities of druglike sub-stances (55).

Improvements in structural biology, morespecifically in nuclear magnetic resonancespectroscopy, robotic crystallization, cryo-genic crystal handling, x-ray crystallography,and high-speed computing have greatly facil-itated protein structure determination (56,57). Indeed, technological advances have pro-pelled structural biology to a position wherethe elucidation of the three-dimensionalstructure of medically relevant proteins on alarge scale appears possible. The feasibilityof this concept of “structural genomics” issupported by the fact that the universe ofcompact globular protein folds is quite limit-ed. It may not exceed 5000 distinct spatialarrangements of peptide chains (58).

Protein-protein interactions, e.g., the bind-ing of immunoglobulin E, vascular endothe-lial growth factor, or IL-2 or IL-5 to theirrespective receptors, may represent very at-tractive drug targets in the case of allergies,cancer, autoimmune diseases, or asthma. Tra-ditional small-molecule drug discovery haslargely failed with these targets. However,protein-protein interfaces have “hot spots,”small regions that are critical to binding andthat have the same size as small molecules.The targeting of these hot spots by smallmolecules may turn out to be capable ofdisrupting undesirable protein-protein inter-actions (59–61).

Eventually, the structure of well-validatedold and new targets should be able to guidethe chemical effort directed at new drugs. Thenovel approaches mentioned above all aim atthis objective.

The Institutional Basis of DrugResearch Will ChangeHistory does not repeat itself—at least notin a simple and linear way. Nevertheless,there are parallels between the drug re-search in 1900 and in the year 2000. Onehundred years ago, an alliance betweenchemistry and pharmacology was createdthat needed much time to develop butturned out to be highly successful. Thepharmaceutical industry provided a homefor this alliance. Today, many additionalforces are at work. As with chemistry andpharmacology during much of the 20th cen-tury, genomics, bioinformatics, and struc-tural genomics will generate unprecedentedresults in the new century. Drug discoveryhas become so complex that it cannot becontained within the confines of the phar-maceutical industry. Discovery and, for thatmatter, drug development need a diversifiedand flexible industrial base. The emergence ofthe biotech industry as a “discovery” industryas well as the establishment of many contractresearch organizations show that free marketswill be capable of generating the technical andinstitutional instruments that are needed to ap-ply scientific advances to the solution of soci-etal problems.

Fig. 4. Example for the identification of “hits” in a high-throughput screening assay that identifiedfive small molecules affecting mitosis. (A) From a whole-cell immunodetection assay, 139cell-permeable compounds were selected that caused increases in phosphonucleolin staining inA549 cells. After eliminating molecules that target pure tubulin, the effect of the antimitoticcompounds on microtubules (green), actin (not shown), and chromatin (blue) distribution wasimaged. Examples of the effects of two different small molecules on BS-C-1 cells in mitosis (upper)and in interphase (lower) are shown. (B) Summary of the screening results. Twelve antimitoticcompounds tested on cells had pleiotropic effects and were not evaluated further. [From (45)]

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R E V I E W

Target-Oriented and Diversity-OrientedOrganic Synthesis in Drug Discovery

Stuart L. Schreiber

Modern drug discovery often involves screening small molecules for theirability to bind to a preselected protein target. Target-oriented synthesesof these small molecules, individually or as collections (focused libraries),can be planned effectively with retrosynthetic analysis. Drug discovery canalso involve screening small molecules for their ability to modulate abiological pathway in cells or organisms, without regard for any particularprotein target. This process is likely to benefit in the future from anevolving forward analysis of synthetic pathways, used in diversity-orient-ed synthesis, that leads to structurally complex and diverse small mole-cules. One goal of diversity-oriented syntheses is to synthesize efficientlya collection of small molecules capable of perturbing any disease-relatedbiological pathway, leading eventually to the identification of therapeuticprotein targets capable of being modulated by small molecules. Severalsynthetic planning principles for diversity-oriented synthesis and their rolein the drug discovery process are presented in this review.

Modern methods for stereoselective organicsynthesis have increased the efficiency withwhich small molecules can be prepared.These compounds include new drugs anddrug candidates and reagents used to explorebiological processes. However, it is a nearly

four-decade-old method for purifying reac-tion products that is currently having thegreatest impact on organic synthesis (1). Sol-id phase organic synthesis (2–7), adapted fromthe original solid phase peptide synthesis (1),promises to increase dramatically the diver-sity and number of small molecules availablefor medical and biological applications.

The evolution of stereoselective organicsynthesis from the solution (8) to the solid(2–7, 9–11) phase has created strategic chal-lenges for organic chemists because it has

provided the means to synthesize not onlysingle target compounds or collections of re-lated targets but also collections of structur-ally diverse compounds. Target-oriented syn-theses are used in drug discovery efforts in-volving preselected protein targets, whereasdiversity-oriented syntheses are used in ef-forts to identify simultaneously therapeuticprotein targets and their small-molecule reg-ulators. Target-oriented synthesis has bene-fited from a powerful planning algorithmnamed retrosynthetic analysis (8); a compa-rable algorithm for diversity-oriented synthe-sis is only now beginning to be developed.Planning diversity-oriented syntheses will be-come increasingly important for organicchemists as methods to screen large collec-tions of small molecules become more effec-tive and routine.

Target-Oriented Synthesis andRetrosynthetic AnalysisTarget-oriented synthesis has a long historyin organic chemistry. In universities, the tar-gets are often natural products, whereas inpharmaceutical companies, the targets aredrugs or libraries of drug candidates. Begin-ning in the mid-1960s, a systematic method

The author is at the Howard Hughes Medical Institute,the Department of Chemistry and Chemical Biology,and the Harvard Institute of Chemistry and Cell Biol-ogy, Harvard University, Cambridge, MA 02138, USA.E-mail: sls@slsiris.harvard.edu

17 MARCH 2000 VOL 287 SCIENCE www.sciencemag.org1964

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