INTRODUCTION

Drug design is the approach of finding drugs by design, based on their biological targets.
Typically, a drug target is a key molecule involved in a particular metabolic or signalling pathway
that is specific to a disease condition or a pathway or to the infertility or survival of a microbial
pathogen. Other approaches may be to enhance the normal pathway by promoting specific
molecules in the normal pathway that may be affected in the diseased state.

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Hit; A term used in high-throughput screening to
describe a compound with improved properties which
will be further developed in the search for a lead
compound.
Lead compound; A chemical compound which has the
desired pharmacological effect but is unsuitable to serve
as a drug. The lead compound provides the base
structure which is then modified by organic chemistry or
enzymes to provide the active pharmaceutical ingredient.
Active pharmaceutical ingredient (API); The final product
in the manufacturing process prior to formulation. API
may also be known as the active ingredient.
Drug substance; The formulated form of the active
pharmaceutical ingredient which is the material given to
a patient. The drug substance may also be known as the
drug product or dosage.
Drug design is more complex than just the development of the pharmacologically active
compound. A lead compound frequently needs to be chemically modified, for example, to
eliminate undesirable side effects or improve pharmacokinetic behavior.In the case of aspirin,
salicylic acid was considered the active ingredient for pain but caused gastric irritation;
acetylation of the o-hydroxyl group provided the therapeutic derivative used today. While some
aspects of the mechanism of action of aspirin are understood, such as acetylation of target
proteins, some newly identified applications in cancer therapy remain poorly understood.

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Another example of the evolution of a natural product to a drug is provided by physostigmine.
Physos-tigmine (eserine) was identified as the active component of the Calabar bean (Esere nut;
Physostigma venenosum) found in tropical Africa. It was known to contain a potent poison.
Work some 60 years ago demonstrated that physostigmine was a competitive inhibitor of
acetylcholine esterase. The early work established physostigmine as a lead compound for a class
of cholinesteric esterase. The early work established physostigmine as a lead compound for a
class of cholinesteric drugs resulting in novel derivatives such as phenserine which is under
consideration for use in Alzheimer disease.

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Another example is provided by thrombin, the final enzyme in the process of blood coagulation.
number of compounds which never became good drugs. Improvements in our understanding of
thrombin have resulted in the development of new drugs which are in fact pro-drugs such as
dabigatran etexilate which inhibit thrombin after hydrolysis by an esterase. drugs resulting in
novel derivatives such as phenserine which is under consideration for use in Alzheimer disease.
 SEARCH FOR LEADS

Through screening process, some compounds emerge with

sufficient activity to warrant further investigation. The active
compounds are then examined against a number of criteria,
including complexity and anticipated pharmacokinetic
behavior. Compounds that satisfy the selection criteria are
called leads and advanced for further optimization of
activity, selectivity, and biological behavior. Occasionally,
leads are found through other methods, such as serendipity
or clinical observations.

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 Approaches to Searching for Hits

The most common tool for discovering hits is library screening.

The library may consist of traditional compounds with
potentially high activity molecules, smaller fragments of less
activity, or even virtual molecules tested through molecular
modeling simulations

1. Traditional Library Screening

The goal of screening of a library, in whole or in part, is to discover

compounds with modest activity against a target. The active
compounds discovered through a screen are called hits. compound
libraries are a vital resource in a productive drug discovery program.
Molecular biological information on a target can advance a drug
search only so far. Random screening of either an entire or partial
library, then, hopefully provides promising hits for the lead
optimization stage.

> In-House Libraries.

> Out-Sourced Libraries

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 2.Fragment-Based Screening
Fragment libraries are no different than traditional compound
libraries except molecules in a fragment library are smaller.
Fragments have a molecular weight of only 120 to 250 g/mol.
Limiting molecular weight dramatically decreases diversity in
the library. Smaller molecules have fewer potential sites for
intermolecular binding than larger molecules. Therefore, small
molecules rarely bind as strongly as larger compounds.
3. Virtual Screening

Virtual screening, sometimes called in silico screening, is a

relatively new approach to library testing. In a virtual screen,
computerized molecular models of both the target and library
member are aligned to determine potential complementary
intermolecular interactions. Molecules with a high level of
complementarity, indicative of potentially strong binding, are
flagged for synthesis and testing. A virtual screen requires
sufficient knowledge about the target protein structure, likely
from x-ray or NMR data.

2.
 FINDING A LEAD COMPOUND

A lead compound is a compound which shows the desired pharmaceutical activity. The level of
the activity may not be very great and there may be undesirable side effects. The lead
compound provides a start for the drug design and development process. There are various
ways in which a lead compound might be discovered:

Combinatorial synthesis

Computer aided design

Serendipity prepared mind

Computerized searching of structural data bases

Designing lead compound by NMR

Screening of natural products

Medical folklore

Screening synthetic compound "libraries ”

Starting from natural ligand or modulator

Existing drugs

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 MOLECULAR MODIFICATION
Molecular modification is chemical alteration of a known and
previously characterized lead compound for the purpose of
enhancing its usefulness as a drug. This could mean enhancing
its specificity for a particular body target site, increasing its
potency, improving its rate and extent of absorption, modifying
to advantage its time course in the body, reducing its toxicity,
changing its physical or chemical properties (like solubility) to
provide desired features. Molecular modification by nature has
been going on since the beginning of life on this planet. In the
relatively short time since chemistry has developed into a
science, chemists had learned well from nature the significance
of small changes in chemical structures of drugs to the biological
activity in living organisms. Let us recall a few examples of
molecular modifications of drugs as they occur in the plant and
animal kingdoms.
 REFERENCE
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Incentive," Hearings before Sub committee on Antitrust
and Monopoly of the Committee on the Judiciary, U. S.
Senate, 87th Congress, First Session, Pursuant to S. Res.
52, on S. 1552, Part 4, Government Printing Office, pp.
2224, 2225, 1961.
2. Hench, P. S., "Molecular Modifications," Hearings
before Subcommittee on Antitrust and Monopoly of
the Committee on the Judiciary, U. S. Senate, 86th
Congress, First Session, Pursuant to S. Res. 57, Part 14,
Administered Prices in the Drug Industry
(Corticosteroids), p. 8172, 1959.
3. J. Am. Med. Assoc., 185, 315 (1963).
4. Modell, Walter, Science 139, 1185 (1963).
New York Academy of Medicine, Committee on Public
Health, Bull. N. Y. Acad.