Virtual Screening and Hit Prioritization

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Virtual Screening and Hit Prioritization

  1. 1. Virtual Screening and Hit Prioritization Dr. Puneet Kacker Amity University Uttar Pradesh pkacker@amity.edu
  2. 2. Drug Discovery Process http://www.lonza.com
  3. 3. What Medicinal Chemists Want? Experiment Identification Binding
  4. 4. The Experimental Method High-throughput screening (HTS) Expensive Time Consuming Skill Intensive
  5. 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. 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. 7. VLS: alternative of HTS V L S Millions of Compounds Few Potential Binders
  8. 8. The Detailed VLS Process Select a Target Select a Compound Library Prepare Target Prepare Ligand set Select a Docking Engine Analyze the Results
  9. 9. Target Selection Take one Disease Search Therapeutic Targets known for that particular disease 1 2
  10. 10. Selecting a Compound Library
  11. 11. Receptor Preparation Add Hydrogen Assign Charges Assign Protonation States Complete Missing Atoms
  12. 12. Ligand Preparation and VLS Filters Preparation Assign charges Generate possible Tautomers and Stereoisomers (LigPrep) Assign right protonation states Filters Physico-Chemical Filters (Lipinski Rule of Five) Similarity-based filters (take only diverse set of compounds)
  13. 13. Docking Engines Free  Vina DOCK ArgusLab Commercial
  14. 14. Cont… Free DOCK AutoDock Vina ArgusLab
  15. 15. VLS Hits Prioritization Clustering Score based
  16. 16. Cont… Interaction-based
  17. 17. Simple Docking Exercise ArgusLab
  18. 18. The Target
  19. 19. ArgusLab Procedure Defining a Binding Site Defining a Ligand Running Docking Simulation Pose Energy 1 2 3 4
  20. 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. 21. Checking the Novelty Scifinder
  22. 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. 23. Reading Material
  24. 24. Journals Publishing Papers on VLS IF: 4.67IF: 1.79 IF:3.15 IF:5.25
  25. 25. Thanks!! pkacker@amity.edu

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