Lead – Definition
A lead is defined as a compound, usually a small organic molecule that demonstrates the desired biological activity on a validated molecular target.
The most important sources of clues are “Libraries” of molecules, eg, natural product libraries, peptide libraries, carbohydrate libraries, etc.
Virtual Libraries can be created using “Combinatorial Chemistry”.
Lead Identification Technologies
Virtual projection.
Chemoinformatics.
Parmacophoran mapping.
Quantitative activity structure relationship.
Virtual projection (VS):
Virtual detection is part of chemoinformatics and is used in lead identification. It involves the detection or docking of compounds based on protein structure and the search for chemical similarity based on small molecules. Important features to consider when developing a VS system are: knowledge about the compounds it can screen against its receptor, knowledge about receptor structure and receptor-ligand interactions in general, and standard knowledge about drugs and characteristics of the receptors. drugs.
Chemoinformatics:
Chemoinformatics combines elements of biology and chemistry with mathematics, statistics, and computer science. Chemoinformatics analyzes focus on various types of large databases, such as macromolecular structures, three-dimensional chemical databases, and compound libraries.
Pharmacophore mapping:
Pharmacophore searching is an approach to identify lead compounds against a desired target. A pharmacophore is the specific three-dimensional arrangement of functional groups within a molecular framework that are required to bind to a macromolecule or to the active site of an enzyme.
Quantitative Structure Activity Relationship (QSAR):
QSAR analysis refers to methods that relate the structural features of molecules to biological activity in quantitative terms. QSAR analysis attempts to establish linear relationships between selected structural features in a series of related molecules and their known level of activity.
Lead Qualities
A leader molecule should have the following desirable qualities:
(a) Potency, i.e., able to modulate the target effectively.
(b) Solubility: It should be easily soluble in water for faster action.
(c) Milder lipophilicity: Ability to penetrate the plasma membrane.
(d) Metabolic stability: It must not be rapidly destroyed within the body.
(e) Bioavailability: faster absorption in the body.
(f) Construction of specific proteins.
(g) Less toxic or not toxic at all.
Lead Compound Optimization
Once candidate drugs are assessed for quality, they are registered as an investigational new drug and submitted for clinical trials.
Stages of clinical trials:
preclinical phase
animal studies
phase I
Normal (healthy) human volunteers
Stage II
Evaluation of safety and efficacy in patients, and selection of the dosage regimen.
phase III
Study of large number of patients with placebo or comparator
Stage IV
Long-term follow-up of adverse reactions reported by pharmacists and physicians.
Summary-The scope of bioinformatics is very broad and provides an opportunity for the development of new drugs. Combinatorial chemistry approaches have made it possible to assemble large chemical libraries for testing.
