AN OVER VIEW OF MODERN DRUG

DISCOVERY PROCESS: LEAD

IDENTIFICATION AND LEAD
OPTIMIZATION

JURUSAN FARMASI
FAKULTAS MATEMATIKA DAN ILMU
PENGETAHUAN
UNIVERSITAS GARUT
2019
Drug Discovery and Drug development

 drug discovery is the process by which new

candidate medications are discovered

 Drug development is the process of bringing

a new pharmaceutical drug to the market
once a lead compound has been identified
through the process of drug discovery
 Lead compound
 chemical compound that has pharmacological or
biological activity likely to be therapeutically
useful
 Also called developmental candidates, because
the discovery and selection of lead compounds
occurs prior to preclinical and clinical
development of the candidate.
 criteria for leads
 Pharmacodynamic properties - efficacy, potency,
selectivity
 Physiochemical properties - water solubility,
chemical stability
 Pharmacokinetic properties - metabolic stability
and toxological aspects.
 Chemical optimization potential - ease of chemical
synthesis and derivatization.
 Patentability
Lead Identification

 Organic compounds are identified which

interact with the target protein and modulate
its activity by using random (screening) or
rational (design) approaches.
High-throughput Screening

 Natural product and synthetic compound

libraries with millions of compounds are
screened using a test assay.
 In theory generating the entire ‘chemical
space’ for drug molecules and testing them
would be an elegant approach to drug
discover
Structure Based Drug Design

 Three dimensional structures of compounds

from virtual or physically existing libraries are
docked into binding sites of target proteins
with known or predicted structure.
 Scoring functions evaluate the steric and
electrostatic complementarity between
compounds and the target protein.
 The highest ranked compounds are then
suggested for biological testing.
Methods of lead
Identification
I)Random screening:
 All compounds including synthetic chemicals,
natural products of plant, marine and
microbial origin from a given series are tested
 Inspite of budgetary and manpower overuse,
this method may be used to discover drugs or
leads that have unexpected activities.
Antibiotics like, streptomycin and
tetracyclines were found out by this method.
ii) Nonrandom screening:
 It is a modified form of random screening
which was developed because of budgetary
and manpower restrictions. In this method,
only such compounds having similar
structural skeletons with that of lead, are
tested.
iii) Drug metabolism studies :
 Structural modifications are done in drug
molecule by the enzymes to increase its
polarity. The discovery of sulfanilamide is
reported through the metabolic studies of
prontosil.
iv) Clinical observations:
 Many times the drug possesses more than
one pharmacological activities. The main
activity is called as therapeutic effect while
rest of the actions is known as side effects of
the drug.
 Such drug may be used as lead compound for
structural modifications to improve the
potency of secondary effects.
Rational approaches to lead
discovery
 The knowledge about the receptors and their
mode of interaction with drug molecules
plays an important role in drug design.
 This knowledge may be used to develop
conformationally bioactive skeletons having
exact three-dimensional complementarity to
a receptor.
 Greater potency, higher selectivity and less
adverse effects are expected by reducing the
flexibility of the drug structure.
 This approach is of greater importance in
identification of lead nucleus.
 It involves the use of signs and symptoms of
the disease.
Lead Optimization

 Molecules are chemically modified and

subsequently characterized in order to obtain
compounds with suitable properties to become a
drug.
 Leads are characterized with respect to
pharmacodynamic properties such as efficacy
and potency in vitro and in vivo, physiochemical
properties, pharmacokinetic properties, and
toxicological aspects.
 Once compounds with desirable in vitro profiles
have been identified, these are characterized
using in vivo models
 Charaterizing Leads
 Potency refers to the amount of drug required for its
specific effect to occur
 Efficacy measures the maximum strength of the
effect itself,at saturating drug concentrations.
 Pharmacokinetics - “what the body does to the
drug.”
 Pharmacodynamics –
 determining the biochemical and physiological
effects of drugs
 the mechanism of drug action and
 the relationship between drug concentration and
effect.
 Lead optimization requires the simultaneous
optimization of multiple parameters and is
thus a time consuming and costly step.
 Methods of Lead Optimization in
Analog Design
1.Identification of the active part
(Pharmacophore).
2. Functional group optimization.
3. Structure activity relationship studies.
4. Bioisosteric replacement.
5. Design of rigid analogs.
6. Homologation of alkyl chains or alteration of chain
branching, design of aromatic ring position isomers,
alteration of ring size, and substitution of an
aromatic ring for a saturated one or the converse.
7. Alteration of stereochemistry, or design of
geometric isomers or stereoisomers.
8. Design of fragments of the lead molecule that
contain the pharmacophoric group (bond
disconnection).
9. Alteration of interatomic distances within the
pharmacophoric group or in other parts of the
molecule.