This document discusses virtual screening and molecular docking techniques used in drug discovery. It notes that virtual screening involves creating a large virtual library that is screened using docking programs to select the most active compounds for laboratory testing. Molecular docking requires knowledge of the 3D structure of the target protein binding site and involves placing flexible ligand molecules into the target's active site to investigate binding interactions and detect new binding pockets in a cost-effective and time-saving approach compared to laboratory high-throughput screening.

1. Docking
Virtual High Throughput In silico screening
Abhijeet Kadam
TSEC
BioTechnology

2. Drug Discovery
● Tedious process
● Many stages
● Lead identification – most imp
● Virtal screening or in silica database screening
used to discover novel lead compound

3. Virtual Screening (VS)
● Many advantages
– Used for lead discovery
– Cost effective
– Good results
– Less time consuming
● In silico virtual HTS = HTS screening
● Accesses new chemical compounds from large
Database (virtual library)

4. Virtual Screening
● Helps select molecules for lab testing
● Exploits structural properties of ligand molecule
(proteins)
● Virtual screening involves
– Creation of large in silico virtual library
– Which is Screened
– Docking program is applied
– Most active momber is selected
– Lab testing

5. HTS
● Thousands of sample screened against target
● Improves lead identification
● Fastens the process

6. VS techniques
● Requires knowlwdge of binding criteria
– Geometry
– Ligand binding
– Molecular similarity
– Biosteric functional group replacement
● 2 fundamental approaches
– 1) docking / molecular docking (3D str available)
– 2) similarity based VS (when 3D str not available)

7. Molecular Docking
● Requires knowlwdge of 3D structure of the target
protein binding site
● Basic requirements
– 1) A target protein structure with/without ligand
– 2) A database of virtual compounds
– 3) A computational framework to work out desired
docking and scoring procedures
● Ligand – flexible
● Protein – rigid

8. Molecular Docking
● Docking performed by placing rigid molecules or
fragments into the targets active site by using
– Clique search
– Geometry configrations
– Pose clustering
● Docking as VS technique
● Many advantages (as discussed)

9. Molecular Docking
● Ligands are designed according to the structure
and modelled as per demand of target binding
pocket
● Docking helps investigate the active site as well
as to detect uncovered binding pockets
● Examples
– GROWMOL – for ligand construction & docking
– Ilib diverse – generates focussed virtual library range

10. After creating virtual library
● Target is prepared
● Compound is docked into target site
● Evaluation for goodness of fit (2steps)
– Docking which include search for conformation and
configuration of ligand
– Scoring which include energies between target and
ligand

11. Scoring
● Of docked poses
● PL interactions
● Difficult step
● 3 methods
– Imperical scoring function – from training sets of PL
– Force feild scoring function – potential energy &
entropy
– Knowledge based Scoring function – atom pair
potentials from structure database

12. Classes of Virtual screening
methods
● Ligand based VS
● Fragment based VS
● Receptor based VS