AStatisticalAnalysisoftheLinearInteraction-DDDC.ppt

Flexible-Protein Docking Dr Jonathan Essex School of Chemistry University of Southampton Southampton Programme Existing small-molecule docking Typical approximations, and outcomes Evidence for receptor flexibility, and consequences Methods for accommodating protein flexibility in docking: The ensemble approach The induced fit approach Existing small-molecule docking Taylor, R.D. et al. J. Comput. Aided Mol. Des. 16, 151-166 (2002) Many docking algorithms (some 127 references in this 2002 review!) Most docking algorithms: Rigid receptor hypothesis Limited receptor flexibility in, for example, GOLD – polar hydrogens Existing small-molecule docking Most docking algorithms: Range of ligand sampling methods Pattern matching, GA, MD, MC… Treatment of intermolecular forces: Simplified scoring functions: empirical, knowledge-based and molecular mechanics Very simple treatment of solvation and entropy, or completely ignored! Existing small-molecule docking And how well do they work? Jones, G. et al. J. Mol. Biol. 267, 727-748 (1997) In re-docking studies, achieved a 71 % success rate This is probably typical of most of these methods So what’s missing? The scoring function Existing functions inadequate Too simplified, for reasons of computational expediency Solvation and entropy often inadequately treated Possible solutions? More physics The rigid receptor hypothesis Murray, C.W. et al. J. Comput. Aided Mol. Des. 13, 547-562 (1999) Docking to thrombin, thermolysin, and neuraminidase PRO_LEADS – Tabu search In self docking, ligand conformation correctly identified as the lowest energy structure – 76 % For cross-docking – 49 % successful Some of the associated protein movements very small The rigid receptor hypothesis Erickson, J.A. et al. J. Med. Chem. 47, 45-55 (2004) Docking of trypsin, thrombin and HIV1-p Self-docking, docking to a single structure that is closest to the average, and docking to apo structures Docking accuracy declines on docking to the average structure, an