title: Cross-docking of inhibitors into CDK2 structures. 2.
abstract: In the preceding paper (Duca, J. S.; Madison, V. S.; Voigt, J. H. J. Chem. Inf. Model. 2008, 48, 659-668), the accuracy of docking and affinity predictions of the Gold and Glide programs were investigated using single protein conformations spanning 150 CDK2/inhibitor crystallographic complexes. High docking accuracy was observed with both methods; furthermore, Glide showed modest log(IC50)/score correlations. In this part of the study, the effect of combining docking results from multiple protein conformations in a consensus fashion was probed. This approach enhanced docking accuracy only for Glide, which was attributed to the nature of its scoring function. For log(IC50)/score correlations, particular emphasis was placed on considering only scores from correctly docked poses. Using multiple instead of single protein structures showed an improvement in the correlations. Validation sets and scrambling experiments were used to examine the statistical significance and predictivity of these correlations. Rather than actual improvements in scoring accuracy, docking to multiple protein conformations produced overfitting artifacts.
authors.affiliation: Department of Drug Design, Schering-Plough Research Institute, 2015 Galloping Hill Road, K15-1-1800, Kenilworth, New Jersey 07033, USA. johannes.voigt@spcorp.com
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Voigt
authors.forename: Carl
authors.initials: C
authors.lastname: Elkin
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Madison
authors.forename: José S
authors.initials: JS
authors.lastname: Duca
mesh_terms: D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009010:Monte Carlo Method; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2