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Transcript of Drug Discovery and Development
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University of Tripoli
Faculty of pharmacy
developmentdevelopment3 rd ear harmac
S. M. Bensaber
Tripoli
2013 / 2014 1
DEVELOPMENT OF DRUGS ( DRUG DESIGN ) 12hrs
A- Sources of Drugs.
1- Natural sources
2- Semisynthetic drugs
3- Synthetic drugs.
B- Genesis of Drugs.
1- Serendipity ( Accidental discovery )
- .
i- Rationally directed random screening .
ii- Rationally directed metabolite approach .
3- Extraction from natural sources.
4- Molecular modifications
i- General processes. ii- Special processes.
- Simplification ( Disjunction).-Replication.
- Hybridization.
-Addition.
-Vinylogy principle- Increase or decrease of the alkyl chain .
- Isosteric substitution ( isosteres and bioisosters).
- Introduction of a bulky group .
C- Soft and hard drugs .
D- Drug latentiation .
- Prodrugs - Bioprecursors - Targeted drugs
E- Anti metabolite approach .
- .
- Others .
iii- Methods of lead optimization.- Topless sequential method ( pi , sigma , Es)
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Drug Discovery & Development:
Human clinical trials
(2-10 years)The discovery phase
The Clinical phase
3
FDA approval
(2-3 years)
Identify disease
The discovery phase
Drug Discovery & Development:
The drug discovery is a lengthy,
expensive, and complicated process,
and validation
Lead discovery &optimisation
Processing
chemistry
that requires the collaboration of a
large number of research scientists
with skills ranging from computational
and structural chemistry, through
synthetic organic chemistry, molecular
Pre-clinical testing
In vitro
Pre-clinical testing
In vivo
cell biology, genomics, proteomics,
physiology, pharmacology, toxicology,
and clinical biochemistry, amongst
others.4
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Identify disease
Selection of a disease target:
Acceptable therapies are available today for many conditions,
e.g. (Antibiotics for bacterial diseases etc, paracetamol /
ibuprofen etc. for moderate pain relief).
New agents must have statistically proven clear advantages
over existing therapy (not just that it is clinically effective).
5
Target identification
and validation
A bio(macro)molecule may be involved in a disease
process, but to be a drug target it has to be validated.
In other words shown to be critical in the disease process.
Useful techniques available are to validate a target such as
Gene knockout and RNA interference.
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Alead compound isa compound from a series of related
Lead discovery &
optimisation
.
This molecule can be characterised, and modified to
produce another molecule with a better profile of wanted
properties to unwanted side effects.
Alead compound is a first foothold on the drug discovery
ladder.
It takes much more effort to make alead compound into a
drug candidate7
TESTING DRUGS
Biological tests are required in order to find lead
compounds and for drug optimisation
Tests can bein vivo orin vitro
A combination of tests is often used in research
programmes
Pre-clinical testing
In vitro
Pre-clinical testing
In vivo
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Tests not carried out on animals/humans
Tests carried out on target molecules (enzymes or receptors)
Cells e. . cloned cells
Pre-clinical testing
In vitro
Tissues (e.g. muscle tissue)
Organs
Micro-organisms (for antibacterial agents)
More suitable for routine testing
Measure the interaction of a drug with the target but not the
ability of the drug to reach the target
Does not demonstrate a physiological or clinical effect(s)
Does not identify possible side effects and effective prodrugs 9
Identify competitive or non competitive inhibition
Enzyme Inhibition Tests
Pre-clinical testing
In vitro Examples
Strength of inhibition measured as IC50
IC50= concentration of inhibitor required to reduce enzyme
activity by 50%
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Not easy to isolate membrane bound receptorsNot easy to isolate membrane bound receptors
Testing with Receptors
Pre-clinical testing
In vitro Examples
Carried out on whole cells, tissue cultures, or isolated organsCarried out on whole cells, tissue cultures, or isolated organs
AffinityAffinity -- strength with which compounds bind to a receptorstrength with which compounds bind to a receptor
EfficacyEfficacy -- measure of maximum biochemical effect resultingmeasure of maximum biochemical effect resulting
from binding of a compound to a receptor.from binding of a compound to a receptor.
PotencyPotency -- concentration of an agonist required to produceconcentration of an agonist required to produce 5050%%of the maximum possible effect.of the maximum possible effect.
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Pre-clinical testing
In vivo
Carried out on live animals or humans
Measure an observed h siolo ical effect
Measure a drugs ability to interact with its target and its
ability to reach that target
Can identify possible side effects
Transgenic animals - genetically modified animals
Drug potency
Therapeutic ratio/index -
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1- Natural sources, 2- Semisynthetic drugs, 3- Synthetic drugs.
Sources of Drugs.
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TARGET DISEASE
Priority for the Pharmaceutical Industry
Can the profits from marketing a new drug outweigh the
cost of developing and testing that drug?
Questions to be addressed
Is the disease widespread?(e.g. cardiovascular disease, ulcers, malaria)Does the disease affect the first world?
(e.g. cardiovascular disease, ulcers)
Are there drugs already on the market?
If so, what are their advantages and disadvantages (e.g.
side effects)
Can one identify a market advantage for a new therapy?
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DRUG TARGETS
A) Lip idsCell membrane lipids
B Proteins
Receptors
Enzymes
Carrier proteins
Structural proteins (tubulin)
C) Nucleic acids
DNA
RNA
D) Carbohydrates
Cell surface carbohydrates
Antigens and recognit ion molecules
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DRUG TARGETS
Between species
Target selectiv ity
,
Identify targets which are unique to the invading
pathogen
Identify targets which are shared but which are
significantly different in structure
Within the bod
Selectiv ity between different enzymes, receptors etc.
Selectivity between receptor types and subtypes
Selectiv ity between isozymes
Organ and t issue selectivity
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The Lead Compound
A compound demonstrating a property likely to betherapeutically useful
The level of activity and target selectivity are not crucial
Used as the starting point for drug design and development
Found by design (molecular modelling) or by screening
compounds (natural or synthetic)
ee o en y a su a e es n or er o n a ea compoun
Active Principle - a compound that is isolated from a natural
extract and which is principally responsible for the extracts
pharmacological activity. Often used as a lead compound.17
Sources of Lead Compounds
A) The Natural World Plantlife (flowers, trees, bushes)Micro-organisms (bacteria, fungi)
Animal li fe (frogs, snakes, scorpions)
Biochemicals (Neurotransmitters, hormones)
B) The Synthet ic World
Marine chemistry (bacteria, fish etc)
Chemical synthesis (traditional)
Combinatorial synthesis
C) The Virtual World
Computer aided drug design
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Identif ication of Lead Compounds
A) Isolation and purificationSolvent-solvent extraction
Chromatography
Distillation
B) Structure determination
Elemental analysis
Molecular weight
Mass s ectrometr
Infra red spectroscopyUltra violet spectroscopy
MNR (1H,13C,2D) spectroscopy
X-Ray crystallography
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1- Natural product screening
I- Discovery and structural modification
of lead compounds
A- Discovery of lead compounds
2- Drug discovery via random screening of synthetic
organic compounds3- Drug discovery via targeted dedicated screening and
rational design
-
5- Drug discovery from the observation of side effects
6- Pharmacophore-based drug design
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PLANT EXTRACTS
-
1- Natural product screening
CINCHONA BARK - Quinine
YEW TREE - Taxol
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PLANT EXTRACTS
WILLOW TREE - SALICYLIC ACID
1- Natural product screening
COCA BUSH - COCAINE
AspirinOH
O OHAceticanhydride O
O OH
CH3
O
Procaine
N
O
H
H
CO2Me
C
O
O
C
O
N
NH2
CH3
CH3
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MICRO-ORGANISMS
S CH3
HHHN
R
O
OOHOOH O
NH2
OHH2N C
HN
NHHN C
NH
NH2H
OHH HO
HH
H
1- Natural product screening
CH3O
CO2H
S
HN H HC
O
R
Cl
OH
NMe2HO Me H
O2N
CH2OH
HO H
OO
OO
H
CHO
OH
H
Me
CH2OH
H
HO
H
OH
H
H
MeHN
H
HPENICILLIN TETRACYCLINES
N OAc
CO2HO
HN H
CO CHCl2
CEPHALOSPORINS
STREPTOMYCIN
CHLORAMPHENICOL
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VENOMS AND TOXINS
C
O
NH
CH C
OHN CH C
O
N
C
O
N
C OH
O
TeprotideTeprotide
1- Natural product screening
H2N CH C
CH2
O
CH2
C
OH
O
NH
CH C
CH2
O
HN
N
C NH
CH C
CH2
CH2
CH2
NH
C
NH2
NH
N
CH2
CH2
C
NH2
O
CHCH3
CH2
CH3
O
C OH
O
Captopril
(anti-hypertensive)
CH3
C N
HS
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ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORSNATURAL LIGANDS FOR RECEPTORS
HOHN
Me
OH
HO
OHHN
A onistA onist
1- Natural product screening
HO
ADRENAL INE
HO
SALBUTAMOL
O NH
OH
AntagonistAntagonistHO
HO
HN
Me
OH
PROPRANOLOLADRENALINE
HNN
Me
S
HN NHMe
CN
CIMETIDINE
HNN
NH2
HISTAMINEAntagonistAntagonist
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2- Drug discovery via random screening of synthet ic
organic compounds
Random screening- only approach before 1935; screen
every compound you have; still a useful approach;
streptomycin and tetracyclines identified in this way
High-throughput Screens (HTS)
Very rapid, sensitive in vitro screens
Can assay 100,000 compounds a day
1990 ~ 200,000 compounds screened per year
~ - compoun s screene per year
2000 > 50 106 compounds screened per year
in a large pharmaceutical company
So far, no increase in rate of the number of drugscoming on the market.
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3- Drug discovery via targeted dedicated screening and
rational design
Nonrandom (or Targeted or Focused) screening - only
screen compounds related to active compounds
Rational approaches- identify causes for disease states:
imbalance of chemicals in the body
invasion of foreign organisms
aberrant cell growth
Structure-Activity Relationships (SARs) & Molecular modelling
use natural receptor ligand or enzyme substrate as the lead;
a known drug also can be used as a lead
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4- Drug discovery via metabolism studies
Drug metabolism studies - metabolites produced are
screened for the same or other activities
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5- Drug discovery from the observation of side effects
Clinical observations- new activities found in clinical trials;
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5- Drug discovery from the observation of side effects
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Determine the effects of structural changes on activity ofdrug:structure-activity relationships (SARs)
6- Pharmacophore-based drug design
the molecule containing the essential organic functional
groups that directly interact with the target active site and
therefore, confers on the molecule the biological activity of
interest.
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If ou know the harmaco hore for our tar et, ou can
Design new structures.
6- Pharmacophore-based drug design
Design: use analyzed data to design new compounds -
hopefully with better properties
Why make new lead compounds? Increase activity (make binding stronger)
Decrease side effects (increase selectivity)
Improve ease and efficiency of administration to patient
Potentiall find a better s nthetic route
create new lead compounds based on the pharmacophore!
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Simple example 1: 3D structures are known (active molecule)1. Data collection: biological activity of lead compound (and
other compounds)
6- Pharmacophore-based drug design
.
pharmacophoric features (superimpose 3D structures & findcommon features)
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6- Pharmacophore-based drug design
Simple example 1:
3. Design new structures. New molecular mimic will be
tested.
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- Simplification ( Disjunction).
i- General processes.
I- Discovery and structural modification of lead
compounds
B- Molecular modifications of lead compounds
-Replication.
- Hybridization.
-Addition.
-Vinylogy principle
- Increase or decrease of the alkyl chain .
ii- Special processes.
- .
- Electron withdrawing and electron donating groups.- Others .
iii- Methods of lead optimization.- Topless sequential method ( pi , sigma , Es)
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1- Simplification ( Disjunction).
i- General processes.
Once a biologically active compound is found, a common first method is
B- Molecular modifications of lead compounds
Example: ergot alkaloids like
to simplify it to determine the essential parts for activity.
For complex molecules, this often leads to easier synthesis.
Will not be successful if all parts of the molecule are needed for activity
bromocriptine were starting points
for simplified synthetic analogs
shown below
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Synthesis & Evaluation simpler analogs of lead compound Ex. Opioid
1- Simplification ( Disjunction).i- General processes.
B- Molecular modifications of lead compounds
through simplification of cocaine
Morphine Cocaine
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1- Simplification ( Disjunction).
i- General processes.
Molecular modif ications
Morphine
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2- Molecular Replication & Hybridizationi- General processes.
-The association of two identical pharmacophoric entities will
B- Molecular modifications of lead compounds
generate an "identical twin drug" which is equivalent to a
homodimer derivative.
-A compound, where two different pharmacological entities are
bounded, is called a "non-identical twin drug" or heterodimer.
- e rs es gn s ra egy s equ va en o a up ca on
dimerization process of an active compound or lead.
-The aim of this approach is the production of a more potent
and/or more selective drug compared to the single entity.
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i- General processes.
2- Molecular Replication & Hybridization
B- Molecular modifications of lead compounds
dual acting drugs
symbiotic approach
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4- Molecular addition:i- General processes.
Weak forces as (electrostatic and hydrogen bonding)
+
B- Molecular modifications of lead compounds
.
Methenamine
N
O+
Methenamine Mandelate
Mandelic acid
N NH
N
OH
O
-
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ii- Special processes.
B- Molecular modifications of lead compounds
1- Increase or decrease of
the alkyl chain .
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2- Vinylogy principle
ii- Special processes.
-The vin lo rinci le was first formulated b Claisen in 1926 who
B- Molecular modifications of lead compounds
observed for formylacetone acidic properties similar to that of acetic acid.
-The vinyl group plays the role of an electron-conducting channel
between the carbonyl and the hydroxyl group.
-The same effect explains the acidity of ascorbic acid.
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2- Vinylogy principle
ii- Special processes.
B- Molecular modifications of lead compounds
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3- Isosteric substitution ( isosteres and bioisosters).ii- Special processes.
Common alterations of compounds: replacement of groups with
B- Molecular modifications of lead compounds
Examples:
OH isosteres: SH, NH2, CH3O isosteres: S, NH, CH2H isostere: F
O NH
NH
.
Isosteres: atoms or groups of atoms which have the same valence
amide pyrrole
45
Classical and non-classical bioisosteres
for the classical ones, where size equivalence is the key, the
ii- Special processes.
B- Molecular modifications of lead compounds
.
The key replacements (for example, the C, O, and N replacements are
seen for three of the classical isosteres: CH3-,- OH,- NH2 for univalent;
-CH2-, -O-, and -NH- for divalent;
and -COCH2-R (ketone), -COOR (ester), and- CONHR (amide) for the
carbonyl containing compounds.
You should also be able to make isosteric replacements for the ring
equ va en s s ng e aroma c r ngs; s ng e a p a c r ngs, or e genera
tricyclic replacement).
For example we could change the ester alcohol oxygen (not the carbonyl
oxygen) with a CH2 (ketone), NH (amide), or S (thioester).
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If you change an O to CH2- sterics same, but no dipole or lone pair
3- Isosteric substitution ( isosteres and bioisosters).ii- Special processes.
B- Molecular modifications of lead compounds
you c ange an o - s er cs eren , u s a one pa r
O NH
NH
OH
S NH
OH
no activity
Example
Propranolol (beta blocker)NH
OH
HN NH
OH
no activity
no activity active(but less thanPropranolol)
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ii- Special processes.
3- Isosteric substitution ( isosteres and bioisosters).
B- Molecular modifications of lead compounds
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Common alterations of compounds: replacement of groups with
ii- Special processes.3- Isosteric substitution ( isosteres and bioisosters).
B- Molecular modifications of lead compounds
bioisosteres.
Bioisosteres - different chemical groups with the same biological activity.
No restriction on sterics and electronics, unlike classical isosteres.
O N
HOH
Propranolol (beta blocker)potent
HOH
Pindololvery potent
NH
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ii- Special processes.
3- Isosteric substi tution ( isosteres and bioisosters).
B- Molecular modifications of lead compounds
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ii- Special processes.4- Ring expansion/contractions - changes geometry
B- Molecular modifications of lead compounds
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5- Ring variations - may add a binding interaction with
heteroatom;
ii- Special processes.
B- Molecular modifications of lead compounds
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6- Extend structure by adding a funct ional group to lead
compound
ii- Special processes.
B- Molecular modifications of lead compounds
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7- Extend or contract linking chain length between groups
ii- Special processes.
B- Molecular modifications of lead compounds
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-Limit number of possible conformations
-
ii- Special processes.
8- Rigidification
B- Molecular modifications of lead compounds
-Locks molecule in most active conformation - more effective
Add a ring
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ii- Special processes.
8- Rigidification
B- Molecular modifications of lead compounds
r g groups
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Add a bulky groups affect conformation; it may affect steric
ii- Special processes.
8- Rigidification
B- Molecular modifications of lead compounds
.
Alter Stereochemistry: usually
different stereoisomers have
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H-bond donor or acceptor
Convert to:
II - Binding role of specific functional groups in a molecule
Binding role of hydroxyl groups:
Methyl ether (no H-bond donor now; may cause steric problem)
An ester (no H-bond donor; poor H-bond acceptor; steric problem)
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Methyl ether (no H-bond donor; still H-bond acceptor; may cause steric
problem)
Binding role of hydroxyl groups:
II - Binding role of specific functional groups in a molecule
An ester (no H-bond donor now; poor H-bond acceptor; may cause steric
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H-bond donor (if N-H is present) or acceptor; ionic (protonation of N to
Binding role of amino groups:
II - Binding role of specific functional groups in a molecule
Convert to:
Amide (no protonation; no H-bond acceptor now; steric problem).
Tertiary amine (no H-bond donor now; still H-bond acceptor; steric).
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Hydrophobic;
Convert to:
Saturated compound (not effective overlap; no pi system; more flexible).
Binding role of aromatic rings, alkenes:
II - Binding role of specific functional groups in a molecule
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H-bond acceptor; dipole-dipole
Convert to:
Alcohol eometr chan e can weaken H-bond or di ole-di ole
Binding role of ketones:
II - Binding role of specific functional groups in a molecule
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Hydrophobics/sterics
Convert to:
Longer (homologation) or differently-branched groups
Binding role of alkyl substituents:
II - Binding role of specific functional groups in a molecule
Alkyl groups most easily modified are
DRUG OR DRUG
O
OR
DRUG
O
R
O
DRUGO
R
HN DRUG
O
NR2
DRUG NCH3
R
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Binding role of alkyl substituents:
II - Binding role of specific functional groups in a molecule
Notes:
Recall impact of lipophilicity on drug transport through body
Changing alkyl groups may also affect the preferred conformation of the
molecule!
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Binding role of alkyl substituents:
II - Binding role of specific functional groups in a molecule
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Example: Nifedipine analogs
CH3
Binding role of alkyl substituents:
II - Binding role of specific functional groups in a molecule
O2N
N CH3H3C
CO2CH3H3CO2C
H
O2N
N CH3H3C
CO2CH3H3CO2C
H
O2N
N CH3H3C
CO2CH3H3CO2C
H
CH3
Chemical synthesis of analogs help validate or refute hypotheses
regarding mechanism of action/mode of binding - part of design
NifedipeneTreats hypertension
Inactivesteric "bump"
InactiveDifferent conformation
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various/ sterics
Convert to:
Same substituents at different locations
Binding role of aryl substituents:
II - Binding role of specific functional groups in a molecule
Substituents may affect each others properties (pKa)
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Binding role of aryl substituents:
II - Binding role of specific functional groups in a molecule
ONR
6
8
7
-Best when substituent was at position 7
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H-bond acceptor; dipole-dipole
Convert to:
Hydrolysis products (but will lose a piece); reduce (no more H-bond
Binding role of amides:
II - Binding role of specific functional groups in a molecule
acceptor
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II - Prodrug The term prodrug, which was used initially by
Albert HI, is a pharmacologically inactive
compound that is converted into an active drug
by a metabolic biotransformation.
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Prodrug can be classified to two classes:
(1) Carrier linked prodrug- Temporary linkage of the active molecule with transport moiety
- Mostly of lipophilic nature
-
- Non toxic
- Ability to ensure the release of active principle
(2) Bioprecursors
- Do not imply a temporary linkage between the active principle & carrier
- Result from molecular modification of active principle- This modification generate new compounds able to be a substrate for the
metabolizing enzymes.
- Metabolite being the expected active principle
- Ability to ensure the release of active principle75
Prodrug
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Prodrugs for improved lipophilicity or permeability
Prodrug: Why
Prodrugs for improved parenteral administration
Prodrugs to exploit carrier-mediated absorption
Prodrugs for other purposes
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Prodrugs for improved lipophilicity or permeability
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Prodrugs for improved aqueous solubility
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Prodrugs for improved parenteral administration
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Prodrugs to exploit carrier-mediated absorption
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Prodrugs for improved ophthalmic and dermal delivery
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Prodrugs for other purposes
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Soft Drugs - These are the oppositeof prodrugs. Thesecompounds are designed and synthesized as ACTIVEACTIVEcompounds that readily undergo metabolic inactivation to
IV - Soft & Hard Drugs
nontoxic products
Hard Drugs - compounds that contain structuralcharacteristics required for activity but are not susceptibleto metabolism
Increased efficiency by avoiding metabolism
o tox c meta o tes are orme
HOWEVER, less readily eliminated due to lack ofmetabolism
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A- Soft Drug
Soft drugs are biologically active drugs
designed to have a predictable and controllable
metabolism to nontoxic and inactive products
after they have achieved their desired
pharmacological effect.
The molecule could be deactivated and
detoxified shortly after it has exerted its
biological effect, the therapeutic index could be
increased, providing a safer drug.85
Advantages of Soft Drug
Elimination of toxic metabolites, thereby increasing the
therapeutic index of the drug;
Avoidance of pharmacologically active metabolites that
can lead to long-term effects; Elimination of drug interactions resulting from
metabolite inhibition of enzymes;
Simplification of pharmacokinetic problems caused by
multiple active species.
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The difference between prodrugs
and soft durgs
The concepts of prodrugs and soft drugs are opposite, as
follow:
A prodrugs is an inactive compound that requires a
metabolic conversion to the active form;
A soft drug is pharmacologically active and uses metabolism
as a means of promoting excretion.
However, it is possible to design a pro-soft drug, a modified
soft drug that requires metabolic activation for conversion to
the active soft drug.
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B- Hard Drugs
Hard drugs are nonmetabolizable compounds,
characterized either by high lipid solubility and
accumu a on n a pose ssues an organe es or
high water solubility. They are poor substrates for the metabolizing
enzymes; the potentially metabolically sensitive
parts of these drugs are either sterically hindered or
the hydrogen atoms are substituted with halogens
to block oxidation.88
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V - QSAR
Quantitative structure-activity relationships
(QSAR) represent an attempt to correlate
structural or property descriptors of compounds
with activities.
These physicochemical descriptors, which include
arameters to account for h dro hobicit
electronic properties, and steric effects, are
determined empirically or, more recently, by
computational methods.89
Activities used in QSAR include chemical
measurements and biological assays.
disciplines, with many pertaining to drug design
and environmental risk assessment.
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VI - Molecular Modeling
A technique for the investigation of molecular structures and
properties using computational chemistry and graphical
visualization techniques in order to provide a plausible
three-dimensional representation under a given set of
circumstances.
Computer simulation of molecular structure, to predict and
sp ay s ape, ca cu a e m n mum energy con orma ons
and dynamic ranges, predict recognition sites, binding
orientations, etc.
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In Silico Design and Virtual Screening Techniques
Several computational chemistry approaches are based on the
availabilities of the target protein structures and known active ligands.
DOCK Receptor-Based Approach
When receptor and ligand structures are both known, the docking
receptor-based approach is the most ideal situation.
The ligand can be docked into the known receptor site and molecularmechanics used to simulate receptorligand interactions and dynamics.
Combinatorial-Based Approach
en recep or an gan s ruc ures are o un nown, v r ua
combinatorial chemistry approaches are used.
In this case, computational chemistry is used both to generate
structures and in parallel to perform chemical similarity and diversity
search analysis before and after combinatorial chemistry-based
experimental HTS.92
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Ligand-Based Approach
When the receptorstructure is unknownbut the ligandstructures are
known, a ligand-based approach is used. This situation represents the
most common case.
De Novo Design-Based Approach
When receptor structure is known and ligand structures are
unknown, de novo design-techniques are used.
In this situation, there is available information about the tar et
receptor, or a similar receptor, but no existing leads that can interactwith the active receptor sites.
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