Virtual Screening and Hit Prioritization

1. Virtual Screening
and
Hit Prioritization
Dr. PuneetKacker
Amity University Uttar [email protected]

2. Drug Discovery Process
http://www.lonza.com

3. What Medicinal Chemists Want?
Experiment Identification Binding

4. The Experimental Method
High-throughput screening (HTS)
ExpensiveTime ConsumingSkill Intensive

5. Why Computational Methods?
Accuracy as good as experimental (not
always!)
Can provide insights at molecular level
Fast
Easy to access
Can easily be automated
Economical

6. Computational Limitations
It only can simulate real conditions if
programmed
Larger systems are less accurate then
smaller systems
Need to be experimentally tested for
accuracy.
Does not look at the whole picture

7. VLS: alternative of HTS
V
L
S
Millions of Compounds
Few Potential Binders

8. The Detailed VLS Process
Select a Target
Select a Compound Library
Prepare Target
Prepare Ligandset
Select a Docking Engine
Analyze the Results

9. Target Selection
Take one Disease
Search Therapeutic
Targets known for
that particular
disease
1 2

10. Selecting a Compound Library

11. Receptor Preparation
Add Hydrogen
Assign Charges
Assign Protonation
States
Complete Missing
Atoms

12. LigandPreparation and VLS
Filters
Preparation
Assign charges
Generate possible Tautomersand
Stereoisomers(LigPrep)
Assign right protonation states
Filters
Physico- Chemical Filters (Lipinski Rule of
Five)

Similarity- based filters (take only diverse set
of compounds)

13. Docking Engines
Free 
Vina
DOCK
ArgusLab
Commercial

14. Cont…
Free
DOCK
AutoDockVina
ArgusLab

15. VLS Hits Prioritization
Clustering Score based

16. Cont…
Interaction- based

17. Simple Docking Exercise
ArgusLab

18. The Target

19. ArgusLabProcedure
Defining a Binding Site
Defining a Ligand
Running Docking Simulation
Pose Energy
1
2
3
4

20. Challenges
Receptor Flexibility can
be tackled effectively by
exploiting Multiple diverse
Conformations of proteins
Multiple ways to
construct the ensemble:
Multiple crystal entries
Snapshots taken from MD
simulations
Figure: Hong and Tang, Biochemistry, Vol. 43, No. 16, 2004

21. Checking the Novelty
Scifinder

22. Writing Manuscript/Report
Stand on the shoulders of giants
Take suggestions and ideas from experts
(poster presentation)
Check Consistency
Select an appropriate journal

“Copyright” does not mean “right to copy ”
(Check plagiarized material)

23. Reading Material

24. Journals Publishing Papers on
VLS
IF: 4.67IF: 1.79 IF:3.15 IF:5.25

25. Thanks!!
[email protected]