title: Ensemble docking into multiple crystallographically derived protein structures: an evaluation based on the statistical analysis of enrichments.
abstract: Docking into multiple receptor conformations ("ensemble docking") has been proposed, and employed, in the hope that it may account for receptor flexibility in virtual screening and thus provide higher enrichments than docking into single rigid receptor structures. The statistical analyses presented in this paper provide quantitative evidence that in some cases docking into a crystallographically derived conformational ensemble does indeed yield better enrichment than docking into any of the individual members of the ensemble. However, these "successful" ensembles account for only a minority of those examined and it would not have been possible to prospectively predict their identity using only protein structural information. A more frequently observed outcome is that the ensemble enrichment is higher than the mean of the enrichments provided by its individual members. An additional and promising finding is that, if a set of known active compounds is available, an approach based on induced-fit docking appears to be a reliable way to construct ensembles which provide relatively high enrichments.
authors.affiliation: Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK. ian.craig@novartis.com
authors.forename: Ian R
authors.initials: IR
authors.lastname: Craig
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Essex
authors.forename: Katrin
authors.initials: K
authors.lastname: Spiegel
mesh_terms: D019540:Area Under Curve; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008958:Models, Molecular; D025341:Principal Component Analysis; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D014584:User-Computer Interface
chemical_list: D011506:Proteins