Molecular docking

significace and methods

1. SIGNIFICANCE AND METHODS OF MOLECULAR DOCKING PRESENTED BY: M.SAI KUMAR I/II M.PHARMACY Y17MPHPY449 DEPARTMENT OF PHARMACOLOGY

2. Contents Introdu c tio n . Definitions. Role of Bioinformatics. Types of Docking. Drug Discovery Process. Types of Docking Softwares. Applications of Docking. Achievements in Docking. Conclusion. References. 2

3. Int r oduction 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. 3

4. Enzyme – inhibitors Receptors - agonists or antagonists Ion channel – blockers Transporter –inhibitors DNA - blockers Drug targets 4

5. 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. What is CADD????? 5

6. 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. Why CADD…? 6

7. Molecular Docking 7

8. What is Docking? Docking attempts to find the “best” matching between two molecules. 8

9. … 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. 9

10. Some other definitions… 10 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.

11. 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. Why is docking important? 11

12. 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. Why We Do Docking? 12

13. Lead generation: Natural ligand / Screening Biological Testing Synthesis of New Compounds Drug Design Cycle If promising Pre-Clinical Studies TRADITIONAL DRUG DESIGN 13

14. Modern Drug Discovery Process Molecular Biology & Protein Chemistry 3D Structure Determination of Target and Target-Ligand Complex Modelling Structure Analysis and Compound Design Biological Testing Synthesis of New Compounds If promising Pr e- Cli n ical Studies Drug Design Cycle Natural ligand / Screening 14

15. Drug targets (usually proteins) Binding of ligand to the target (docking) “rational” drug design (benefits = saved time and ₨₨₨ ) Structure-based Drug Design (SBDD) & 15

16. 16 Ligand database Target Protein Molecular docking Ligand docked into protein’s active site Structure-based Drug Design (SBDD) Pharmacokinetic and Pharmacodynamic optimization

17. Applications of Bioinformatics Biot e chnology Pharma Industry/ Molecular Medicine 17

18. Types of Docking 18 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.

19. Types of Docking studies Protein-Protein Docking Both molecules are rigid Interaction produces no change in conformation Similar to lock-and key model 19

20. Continued… 22 Protein-Ligand Docking Ligand is flexible but the receptor protein is rigid. Interaction produces conformational changes in ligand.

21. 21 Some “real” Docking Thermolysin protein with one of its known inhibitors

22. Available Docking Software… 1. DOCK (1982,2001) 2. FlexX (1996) Hammerhead (1996) 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)

23. 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. Application of Molecular Docking in Modern Drug Discovery

24. Application of Molecular Docking in Modern Drug Discovery 24 Case Study- Identification of Inhibitors for Simultaneous Inhibition of Anti- Coagulation and Anti-Infamatory Activities of Snake venom Phospholipase A2. (1994) 169000 compounds Pharmacophore Based-screening 300 compounds Molecular docking 32 promising compounds

25. Growing Evidence of Achievements….!! Molecular Docking has resulted in several breakthrough classes of new drug. 25 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

26. Growing Evidence of Achievements….!! Discovery of Indinavir, the HIV protease inhibitor. (1992) Identification of Haloperidol as a lead compound in a structure- based design for non-peptide inhibitor of HIV. Carbonic Anhydrase (treatment of glaucoma) (2002) Renin (treatment of hypertension) Dyhrofolate reductase (antibacterial) (1992) Neuraminidase (antiviral) HI V -1 asp a r t ic p rot e i n ase ( a n t i - a cq u i r ed i m m uno d efi c i e n cy syndrome) 26

27. Trypanosomal glyceraldehyde-3-phosphate dehydrogenase (anti-parasitic) Thymidylate synthase and purine nucleoside phosphorylase (anticancer) Elastase (treatment of emphysema) Collagenase (Rheumatoid and Osteoarthritis) Phispholipase A2 (anti inflammatory) (1994) Glycogen phosphorylase (treatment of diabetes mellitus) Thrombine (1996) Growing Evidence of Achievements…. !! 27

28. Co n clusion… 28 Molecular docking give the promising contributions to identification and optimization of ligand in modern drug discovery. 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. Docking-based virtual screening lead to much higher hit rate than traditional screening methods. (e.g., HTS)

29. Future Directions 29 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.

30. References 30 Graham L. Patrick, An Introduction to Medicinal Chemistry 4 th 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.

31. Question plssssssssssssssssssss …….. 31