Virtual screening to enrich a compound collection with CDK2 inhibitors using docking, scoring, and composite scoring models

Docking programs can generate subsets of a compound collection with an increased percentage of actives against a target (enrichment) by predicting their binding mode (pose) and affinity (score), and retrieving those with the highest scores. Using the QXP and GOLD programs, we compared the ability of six single scoring functions (PLP, Ligscore, Ludi, Jain, ChemScore, PMF) and four composite scoring models (Mean Rank: MR, Rank‐by‐Vote: Vt, Bayesian Statistics: BS and PLS Discriminant Analysis: DA) to separate compounds that are active against CDK2 from inactives. We determined the enrichment for the entire set of actives (IC50 < 10 μM) and for three activity subsets. In all cases, the enrichment for each subset was lower than for the entire set of actives. QXP outperformed GOLD at pose prediction, but yielded only moderately better enrichments. Five to six scoring functions yielded good enrichments with GOLD poses, while typically only two worked well with QXP poses. For each program, two scoring functions generally performed better than the others (Ligscore2 and Ludi for GOLD; QXP and Jain for QXP). Composite scoring functions yielded better results than single scoring functions. The consensus approaches MR and Vt worked best when separating micromolar inhibitors from inactives. The statistical approaches BS and DA, which require training data, performed best when distinguishing between low and high nanomolar inhibitors. The key observation that all hit rate profiles for all four activity intervals for all scoring schemes for both programs are significantly better than random, is evidence that docking can be successfully applied to enrich compound collections. Proteins 2005. © 2005 Wiley‐Liss, Inc.