Cross-Docking of Inhibitors into CDK2 Structures. 2

• Published in: Journal of chemical information and modeling Vol. 48; no. 3; pp. 669 - 678
• Main Authors: Voigt, Johannes H, Elkin, Carl, Madison, Vincent S, Duca, José S
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.03.2008
• Subjects: Accuracy; Correlation analysis; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - chemistry; Molecular structure; Monte Carlo Method; Protein Conformation; Protein Kinase Inhibitors - pharmacology; Proteins; Studies
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci700428d

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.