Drug Discovery – Lead Identification and Optimization

Drug Discovery – Lead Identification and Optimization

Lead – Definition

A Lead is defined as a compound, usually a small organic molecule that demonstrates desired biological activity on a validated molecular target.

The most important sources of leads are “Libraries” of molecule e.g. natural product libraries, peptide libraries, carbohydrates libraries, etc.

Virtual libraries can be created by using “Combinatorial Chemistry.”

Technologies in Lead Identification

Virtual Screening.


Parmacophore Mapping.

Quantitative structure activity Relationship.

Virtual Screening (VS):

Virtual screening is apart of chemoinformatics and is used in Lead identification. It involves protein structure based compound screening or docking and chemical-similarity search based on small molecules. Important features to be considered while developing a VS system are: knowledge about the compounds that you may screen against your receptor, knowledge about the receptor structure and receptor-ligand interactionsin general and standard knowledge about drugs and drug characteristics.


Chemoinformatics combines elements of biology and chemistry with mathematics, statistics and computer science. Analyses in Chemoinformatics focuses on several types of large databases such as macromolecular structures, 3-D chemical databases and compound libraries.

Pharmacophore Mapping:

The Pharmacophore search is an approach to identify lead compounds against a desired target. A pharmacophore is the specific 3-D arrangement of functional groups within a molecular framework that are necessary to bind to a macromolecule or an enzyme active site.

Quantitative structure activity relationship(QSAR):

QSAR analysis refers to methods that relate structural features of molecules to biological activity in quantitative terms. QSAR analysis tries to establish linear relationships between selected structural features in a series of related molecules and their known level of activity.

Qualities of Lead

A lead molecule should have the following desirable qualities:

(a) The potency i.e. able to modulate the target effectively.

(b) Solubility: It should be easily soluble in water for quicker action.

(c) A milder Lipophilicity: Ability to penetrate plasma membrane.

(d) Metabolic stability: Should not get destroyed quickly inside the body.

(e) Bioavailability: quicker absorption into the body.

(f) Specific protein building.

(g) Less toxic or not at all toxic.

Optimization of Lead Compound

Once the candidate drugs are assessed for quality they are registered as an investigational new drug and submitted for clinical trials.

Stages of clinical trials:

Pre-clinical phase

Studies using animals

Phase I

Normal (healthy) human volunteers

Phase II

Evaluation of safety and efficacy in patients, and selection of dose regimen.

Phase III

Large patient number study with placebo or comparator

Phase IV

Long term monitoring for adverse reactions reported by pharmacists and doctors.

Summary-The scope of Bioinformatics is vast and provides an opportunity for development of new drugs. Combinatorial chemistry approaches has made possible the assembly of large chemical libraries for testing.

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