Presentation on MOLECULAR DOCKING AND RELATED DRUG DESIGN ACHIEVEMENTS

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2. Presented by:
Guided by:
Mr. Santosh Sahadeo Kumbhar
M. Pharm.(Sem-I)
Dr. M. S. Bhatia
Head of Department
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY.
BHARATI VIDYAPEETH COLLEGE OF PHARMACY,
KOLHAPUR.
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3. Contents
Introduction.
Definitions.
Role of Bioinformatics.
Introduction
Types of Docking.
Drug Discovery Process.
Types of Docking Softwares.
Applications of Docking.
Achievements in Docking.
Conclusion.
References.
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4. Abbreviations
CADD
- Computer Aided Drug Design.
QSAR
- Quantitative Structure Activity Relationship.
SARs
- Structure-Activity Relationships.
HTS
-
High Through put Screening.
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5. Introduction
• Drug discovery  take years to decade
for discovering a new drug and very
costly
• Effort  to cut down the research
timeline and cost by reducing wet-lab
experiment  use computer modelling.
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6. Drug targets
•
•
•
•
•
Enzyme – inhibitors
Receptors - agonists or antagonists
Ion channel – blockers
Transporter –inhibitors
DNA - blockers
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7. What is CADD?????
Computational Chemistry/CADD is the chemistry
whose major goals are to create efficient mathematical
approximations and computer programs that calculate the
properties of future drug molecules and thus helping in the
process of drug design and discovery.
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8. Why CADD…?
Drug Discovery today are facing a serious challenge
because of the increased cost and enormous amount of time
taken to discover a new drug, and also because of rigorous
competition amongst different pharmaceutical companies.
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9. Molecular Docking
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10. What is Docking?
Docking attempts to find the “best” matching between two
molecules.
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11. … a more serious definition…
Given two biological molecules determine:
- Whether the two molecules “interact”
- If so, what is the orientation that maximizes the
“interaction” while minimizing the total “energy” of the
complex.
• Goal: To be able to search a database of molecular
structures and retrieve all molecules that can interact
with the query structure.
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12. Some other definitions…
Ligand or key – The complementary partner molecule
which binds to the receptor. Ligands are most often
small molecules also other biopolymer.
Receptor or lock – The "receiving" molecule, most
commonly a protein or other biopolymer.
Docking – Computational simulation of a candidate
ligand binding to a receptor.
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13. Why is docking important?
• It is the key to rational drug design.
• The results of docking can be used to find
inhibitors for specific target proteins and thus
to design new drugs.
• It is gaining importance as the number of
proteins whose structure is known increases.
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14. Why We Do Docking?
• Drug discovery costs are too high: ~$800 millions, 8~14 years,
~10,000 compounds (DiMasi et al. 2003; Dickson & Gagnon
2004)
• Drugs interact with their receptors in a highly specific and
complementary manner.
• Core of the target-based structure-based drug design (SBDD)
for lead generation and optimization.
Lead is a compound that
– shows biological activity,
– is novel, and
– has the potential of being structurally modified for
improved bioactivity, selectivity.
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15. TRADITIONAL DRUG DESIGN
Lead generation:
Natural ligand / Screening
Biological Testing
Drug Design Cycle
If promising
Synthesis of New Compounds
Pre-Clinical Studies
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16. Modern Drug Discovery Process
Natural ligand / Screening
Molecular Biology & Protein Chemistry
3D Structure Determination of Target
and Target-Ligand Complex
Modelling
Drug Design Cycle
Structure Analysis
and Compound Design
Biological Testing
If promising
Synthesis of New Compounds
Pre-Clinical
Studies
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17. Structure-based Drug Design (SBDD)


Drug targets (usually proteins)
Binding of ligand to the target (docking)
“rational” drug design
(benefits = saved time and ₨₨₨)
&
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18. Structure-based Drug Design (SBDD)
Ligand database
Target Protein
Molecular docking
Ligand docked into protein’s active site
Pharmacokinetic and Pharmacodynamic optimization
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19. Applications of Bioinformatics
Pharma Industry/
Molecular Medicine
Biotechnology
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20. Types of Docking
There are 2 types of docking,
1.Rigid docking
2.Flexible docking
Rigid Docking
In the rigid docking molecules are rigid, in 3D space of one of the molecule which
brings it to an optimal fit with the other molecules in terms of a scoring function.
Flexible Docking
In flexible docking molecules are flexible ,confirmations of the receptor and the
ligand molecules , as they appear in complex.
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21. Types of Docking studies
Protein-Protein Docking
Both molecules are rigid
Interaction produces no change in conformation
Similar to lock-and key model
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22. Continued…
Protein-Ligand Docking
Ligand is flexible but the receptor protein is rigid.
Interaction produces conformational changes in ligand.
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23. Some “real” Docking
Thermolysin protein with one of its known inhibitors
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24. ‹#›

25. Available Docking Software…
1. DOCK (1982,2001)
2. FlexX (1996)
3. Hammerhead (1996)
4. Surflex (2003)
5. SLIDE (2002)
6. AutoDock (1990,1998)
7. ICM (1994)
8. MCDock (1999)
9. GOLD (1997)
10.GemDock (2004)
11.FRED (2002)
12.Glide (2004)
13.Yucca (2005)
14. vLife(Biopredicta)
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26. Application of Molecular Docking in
Modern Drug Discovery
• Determine the lowest free energy structures for the receptor
ligand complex.
• Search database and rank hits for lead generation.
• Calculate the differential binding of a ligand to two different
macromolecular receptors.
• Study the geometry of a particular complex.
• Propose modification of a lead molecules to optimize potency
or other properties.
• de novo design for lead generation.
• Library design.
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27. Application of Molecular Docking in
Modern Drug Discovery
Case StudyIdentification of Inhibitors for Simultaneous Inhibition of AntiCoagulation and Anti-Infamatory Activities of Snake venom
Phospholipase A2. (1994)
169000 compounds
Pharmacophore Based-screening
300 compounds
Molecular docking
32 promising compounds
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28. Growing Evidence of Achievements….!!
Molecular Docking has resulted in several breakthrough classes of
new drug.
Drug
Target
Company
Dorzolamid
Carbonic anhydrase
(Hypercapnic Vantilatory
failure)
Merck Sharp and Dohme
(Harlow, UK)
Saquinavir
HIV protease
Roche (Welwyn, UK)
Relenza
Neuraminidase
Biota (Melbourne,
Australia
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29. Growing Evidence of Achievements….!!
1. Discovery of Indinavir, the HIV protease inhibitor. (1992)
2. Identification of Haloperidol as a lead compound in a structurebased design for non-peptide inhibitor of HIV.
3. Carbonic Anhydrase (treatment of glaucoma) (2002)
4. Renin (treatment of hypertension)
5. Dyhrofolate reductase (antibacterial) (1992)
6. Neuraminidase (antiviral)
7. HIV-1 aspartic proteinase (anti-acquired immunodeficiency
syndrome)
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30. Growing Evidence of Achievements…. !!
8. Trypanosomal glyceraldehyde-3-phosphate dehydrogenase
(anti-parasitic)
9. Thymidylate synthase and purine nucleoside phosphorylase
(anticancer)
10. Elastase (treatment of emphysema)
11. Collagenase (Rheumatoid and Osteoarthritis)
12. Phispholipase A2 (anti inflammatory) (1994)
13. Glycogen phosphorylase (treatment of diabetes mellitus)
14. Thrombine (1996)
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31. Conclusion…
1.Molecular docking give the promising contributions to identification
and optimization of ligand in modern drug discovery.
2.The combination of the chemical information of natural products
with docking-based virtual screening will play an important role in
drug discovery in the post-genomic era as more and more new
potential targets emerge from the functional genomic studies.
3.Docking-based virtual screening lead to much higher hit rate than
traditional screening methods. (e.g., HTS)
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32. Future Directions
Pharmaceutical history indicated that natural products provided a
large number of drugs to the market. But, even for the currently used
drug targets, available natural products have not been tested
completely.
Computational medicinal methods, can contribute its unique role in
achieving the task of examining the interaction of all existing
natural products with all possible targets and establishing thier
rational use.
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33. References
Graham L. Patrick, An Introduction to Medicinal Chemistry 4th
edition, 2012 pag. No. 352-356
Dr. Abdul Wadood , Molecular docking and its application
toward modern drug discovery Dept. of Biochemistry Abdul
Wali Khan University.
Dr. Kumud Sarin, Bioinformatics and its Application in Drug
Designing.
E.M. Krovat, T. Steindl and T. Langer, Recent Advances in
Docking and Scoring,2005 Bentham Science Publishers Ltd.
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34. Question plssssssssssssssssssss……..
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