title: Multiple active site corrections for docking and virtual screening.
abstract: Several docking programs are now available that can reproduce the bound conformation of a ligand in an active site, for a wide variety of experimentally determined complexes. However, these programs generally perform less well at ranking multiple possible ligands in one site. Since accurate identification of potential ligands is a prerequisite for many aspects of structure-based drug design, this is a serious limitation. We have tested the ability of two docking programs, FlexX and Gold, to match ligands and active sites for multiple complexes. We show that none of the docking scores from either program are able to match consistently ligands and active sites in our tests. We propose a simple statistical correction, the multiple active site correction (MASC), which greatly ameliorates this problem. We have also tested the correction method against an extended set of 63 cocrystals and in a virtual screening experiment. In all cases, MASC significantly improves the results of the docking experiments.
authors.affiliation: Array BioPharma Inc., 3200 Walnut St, Boulder, Colorado 80301, USA. gvigers@arraybiopharma.com
authors.forename: Guy P A
authors.initials: GP
authors.lastname: Vigers
authors.forename: James P
authors.initials: JP
authors.lastname: Rizzi
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D004791:Enzyme Inhibitors / Q000737:chemistry; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D013223:Statistics as Topic; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D011506:Proteins; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases