Computer Aided Drug Design/Discovery : An Overview

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Computer Aided Drug Design/Discovery : An Overview

  1. 1. “Science is for Society not for Publications”Computer Aided Drug Designing in Biology Girinath G Pillai, Research Fellow, State Inter University Centre of Excellence in Bioinformatics, University of Kerala. Thiruvananthapuram. giribio@scientist.com http://giribio.weebly.com
  2. 2. Overview• Introduction• Drug Discovery• Virtual Screening – Types – Screening Process• Discovery of New Inhibitors• Interpretations• Tools / Softwares• Summary3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 2
  3. 3. Bioinformatics ?
  4. 4. Why? & Where?
  5. 5. Molecular Biology; Information Science3/21/2011 1:25 PM Girinath @ T.K.M. College of Arts & Science 6
  6. 6. Biological Data3/21/2011 1:25 PM Girinath @ T.K.M. College of Arts & Science 7
  7. 7. Drug Discovery Process• Most drug molecules inhibit the activity of a specific protein by blocking its active site.• Examples of proteins targeted by drugs. • HIV protease (ritonavir, viracept….) • Dihydrofolate reductase Target Lead Lead Pre-Clinical Clinical Market discovery Identification Optimization test Trials Entry3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 8
  8. 8. 3/21/2011 1:25 PM Girinath @ Mar Thoma College 9
  9. 9. Discovering Lead Compounds VS/HTS3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 10
  10. 10. 3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 11
  11. 11. Computer Aided Drug Designing• Why does it bind in this way?• How can we make tighter binding, more specific compounds?3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 12
  12. 12. Advantages of Virtual Screening• “hit” or success rate can be 10 – 30%, whereas in HTS it is usually <0.1%• avoids the cost of assaying compounds that do not fit the binding site.• provides a clear structural hypothesis for ligand binding mode and interactions with the protein.3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 13
  13. 13. Virtual ScreeningLigand-based virtual screening• The 3D structure of the biological target is unknown and a set of geometric rules and/or physical-chemical properties (pharmacophore model) obtained by QSAR studies are used to screen the database.Structure-based virtual screening• It involves molecular docking calculations between each molecule to test and the biological target (usually a protein). To evaluate the affinity a scoring function is applied. The 3D structure of the target must be known.3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 14
  14. 14. Ligand Based• 3D-QSAR method that search for relationship between the biological activity of a set of compounds (with specified alignment) and their three-dimensional physicochemical properties (so-called molecular fields).3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 15
  15. 15. Structure based + Docking software Ligand Receptor• The complex quality is evaluated by the score.3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 16 Ligand – receptor complex
  16. 16. How Protein is a Target/Receptor?• Similarity Analysis• Motif Identification• Subcellular Location• Instability Index• Aliphatic Index• Half Life Period• Protein Surface Scan• Secondary Structure Analysis• Modelling & Simulation• Electrostatic Analysis3/21/2011 1:25 PM 17 Girinath G. Pillai @ VIT, Vellore
  17. 17. Automated docking methods• The scoring (or energy) function.• The stratergy used to search for the lowest score3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 18
  18. 18. Docking Tools Ligand flexibility Suitability for Method Scoring function sampling large-VS Force field or Dock Incremental build High contact score FlexX Incremental build Empirical score High Conformational Slide Empirical score High ensembles Conformational Gaussian score or Fred High ensembles empirical scores Gold Genetic algorithm Empirical score Low Glide Exhaustive search Empirical score Low AutoDock Genetic algorithm Force field Low LigandFit Monte Carlo Empirical score Low Pseudo-Brownian Mixed force field ICM sampling local and empirical Low minimization score QXP Monte Carlo Force field Low3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 19
  19. 19. Molecular Docking 3/21/2011 1:25 PM Girinath @ Mar Thoma College 20
  20. 20. Virtual Screening Computational or in silico analog of biological screening ACD WDI NCI X-ray Crystallography NMR homology modeling Ranking HITS3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 21
  21. 21. Docking Process - Conformers Kubinyi, H.: “Success Stories of Computer-Aided Design”, in: Computer Applications in Pharmaceutical Research and Development, Sean Ekins (Ed.), Wiley3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 22
  22. 22. Docking Search Method3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 23
  23. 23. Dynamics & Simulation3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 24
  24. 24. Thank You www.giribio.weebly.com3/21/2011 1:25 PM Girinath G. Pillai @ VIT, Vellore 25

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