... insilicodrugdesigin

1. In silico DRUGDESIGNING
DEVESH SHUKLA

2. WHAT ARE DRUGS ?
•A chemical substance that affects the
processes of the mind or body which is
used in
Diagnosis
Treatment
Prevention
of disease or other abnormal condition.

3. Drug Discovery & Development
Identify disease
Isolate protein
involved in
disease (2-5 years)
Find a drug effective
against disease protein
(2-5 years)
Preclinical testing
(1-3 years)
Formulation
Human clinical trials
(2-10 years)
Scale-up
FDA approval
(2-3 years)
A new drug currently costs ~$880 million and takes ~15-16 years to develop

4. Drug Designing
Drug designing, is the inventive process of
finding new medications based on the
knowledge of a biological target.

5. Drug designing…..
Selected/designed molecule
should be:
Organic small molecule.
Complementary in shape to
the target.
Oppositely charge to the bio
molecular target .

6. Drug designing…..
This molecule will:
 interact with target
 bind to the target
activates or inhibits the
function of a biomolecule
such as a protein

7. IN SILICO DRUGDESIGNING
•In Silico is an expression used to
mean “performed
on computer or via computer
simulation.”
•In Silico drug designing is
defined as the identification of
the drug target molecule by
employing bioinformatics tools .

8. TYPES OF IN SILICO DRUGDESIGNING
IN SILICO
DRUG
DESIGNING
LIGAND BASED
DRUG
DESIGNING
STRUCTURE
BASED DRUG
DESIGNING

9. Structure-based
know receptor,
don’t known ligands
Two pathways to drug discovery / drug design
?
What will be happy in there?
Ligand-based
don’t know receptor,
known ligands
Protein/ligand interactions
structure/biophysics
docking
Statistical analysis of what group(s) are
important for biological activity

10. Ligand based drug design
•Ligand-based drug design relies
on knowledge of other
molecules that bind to the
biological target of interest
• Used to derive a
pharmacophore

11. Structure based drug design
Structure-based drug design
relies on knowledge of the
three dimensional structure
of the biological target
obtained through methods
such as
 x-ray crystallography
 NMR spectroscopy.
homology modeling

12. Structure based drug design…..
• Using the structure of the
biological target, drugs that are
predicted to bind with to the target
may be designed using
 interactive graphics
the intuition of a medicinal
chemist.
automated computational
procedures

13. Basic Steps in In Silico DrugDesigining

14. Selection of disease
• Determine the biochemical basis of the disease process.
• Know the exact step(s) in the pathway that are altered in the
diseased state.
•Knowledge about the regulation of the pathway is also
important. Finally, one would know the three- dimensional
structures of the molecules involved in the process.

15. Target selection
• Biochemical pathways could become abnormal and
result in disease.
• Select a target at which to disrupt the biochemical
process.
Categories of targets
Target for mechanistic drug design usually fall into
three category:
enzymes
receptors
nucleic acids.

16. Target Validation:
• Perform the protein BLAST for all the
genes/proteins with respect to Homo
sapiens.
• Select the least matching molecule in
human and again perform the BLAST.
• As the query sequence matched best ,
so we selected our target molecule and
its structure can be obtained from
RCSB(The Research Collaboration for
Structural Bioinformatics) PDB(Protein
Data Bank).

17. STRUTURE DETERMINATION
• Crystal structure of target protein can be taken from
PDB database

18. Selection of ligands/drugs
• Also called as Lead Identification
• High throughput screening of natural product
and synthetic compound libraries is carried to
screen out lead compound.
• 3D Structure of
compound and
target is docked
Docking
Scoring
• Scoring function
evaluates
comple-
mentarity
• Hits fulfil certain
criteria and then
selected as
leads
Selection

19. Criteria to be fulfilled…..
• Efficacy
• Potency
• Lipinski’s “rule of five”
• Chemical stability
Phamacodynamic
Properties
Physiochemical
Properties
• Metabolic Stability
• Toxicological Aspects
Pharmacokinetic
Properties
• Ease of chemical synthesis
Chemical Optimization
Potential
Patentability
Lead
Compound

20. Determination of active site of targetprotein
• Active site is determined and visualized on
PYMOL

21. Molecular Docking
save
Ligand before and after docking
CADD Software YES Target
Drug
NO
OK
BETTER

22. Scoring functions
Quantify the energy of protein/ligand interactions such as:
Hydrogen bond
Electrostatics
Van der Waals
Hydrophobic
 etc …
PROTEIN
LIGAND
Scoring

23. Lead Optimization
• Refining the 3D
structure of the
lead
compounds.
• Technique used
is QSAR.

24. Preclinical and Clinical Development
Preclinical
Trial
• In vitro studies on animal
• Efficacy and Pharmacokinetic Information
• 3 Phases
Clinical Trial • Safety and Efficacy on Human Beings
File NDA
• Document submitted to FDA for review
• FDA approval

25. CONCLUSION
• In the selection of new drug candidates, manyefforts
are focused on the early elimination of compounds
that might cause several side effects or interact with
other drugs. In silico techniques help in this regard
and they are going to become a central issue in any
rigid drug discovery process.
• In silico technology alone cannot guarantee the
identification of new, safe and effective lead
compound but more realistically future success
depend on the proper integration of newpromising
technologies with the experience and strategies of
classical medicinal chemistry

26. References
• Review Papers
• In Silico Methods in Drug Discovery - A Review by D.
Pugazhendhi and T.S. Umamaheswari.
• An Insight to Drug Designing by In Silico approach in
Biomedical Research by Chethan Kumar S.
• Websites
• http://www.genengnews.com/gen-articles/drug-discovery-
successful-lead-optimization-strategies/1825/
• http://www.gelifesciences.com/webapp/wcs/stores/servle
t/CategoryDisplay?categoryId=1309494&catalogId=10102
&productId=&top=Y&storeId=11765&langId=-1
• www.google.co.in
• www.en.wikipedia.org