This document discusses the history and concepts of molecular modelling in drug design. It describes how early drug design involved trial and error methods to find biologically active molecules through random screening. The development of X-ray crystallography in the 1970s allowed visualization of 3D molecular structures, advancing drug design. Molecular modelling uses computer techniques based on chemistry and experimental data to analyze molecules and predict properties. The first generation of rational drug design used quantitative structure-activity relationships based on 2D structures. The second generation involves molecular modelling to simulate molecular interactions and design molecules meeting biological requirements through direct and indirect approaches as well as database searches and 3D computer-aided drug design.

1. 1
Molecular modelling
Introduction
Abhijeet Kadam
TSEC
BioTechnology

2. 2
Pre Bioinformatics Era
● Take a lead molecule
● Develop a chemical program
● Find analog molecules exibiting desired biological
properties
● Hope to find a molecule of use by 'chance observation or
'random screening'
● This involved trial & error method
● In-vitro + In Vivo
● Expensive
● Ineffecient
Yet we have so many drugs available today.

3. 3
Pre Bioinformatics Era
● Fischer (1894) & Ehrlich (1609) introduces the
concept of 'Lock & Key' model
● 1970's – X-ray crystallography developed
● Hence the 3D structures of molecules
● And advancements in Drug Design

4. 4
Concept of MM
● New molecules conceived on basis of similarity
with known reference structure
or
● On basis of the comlementarity of 3D structure
of Known molecules

5. 5
Concept of MM
● Molecular interactions are fixed
● Hence, MM is a discipline that contributes to the
understanding of these processes in qualitative
and quantative manner.
● Computerized techniques – based on chemistry
methods and expt. Data
● Used to analyze – molecules and moleculars
systems
or
● to predict molecules and biological properties

6. 6
1st
Generation of Rational Approach
in DD
● Rational DD – based on concept that biological
properties of molecules are related to their structural
features
● In 1970's – 2D structures were considered to be final.
● Then came QSAR – quantative str-activity relationship
● This became famous
● Got implemented in computers
●
Which gave us 1st
Gen CADD
● By Hansch and group (fujita, 1990)

7. 7
● Based on –
➔ Mathametical equations
➔ expressing biological activity
➔ in terms of molecular parameters
➔ Such as log p (partition coefficient)
➔ Es (Steric constant)
➔ MR (Molar refractivity) etc...
● But this proved helpful only for optimization based
on 2D formula and fixed 2D frame

8. 8
2nd
Generation : Molecular Modelling
A) Conceptual Frame
B) Fields covered

9. 9
Conceptual Frame
● Uses DD concept of lock and key. It works.
● Here imagination and intution is very important
● You have to imagine or visualize a molecular structure
● Molecular modelling
– Small molecules
● MM of sets of small molecules
– Macromolecules
● Ligand-receptor fir analysis
● Direct + Indirect
– Molecule design confirming requirements

10. 10
Fields Covered
1) Direct DD –
Expt.proven date (X-ray str.)
2) Indirect DD –
Stereochemical and physciochemical features
lead designed by pharmacophore
3) Database searches –
search online wrt pharmacophore
4) 3D – CADD –
generated by computers (macheine learning)
5) Molecular Mimicry –
mimics of known reference compound