Efficacy and selectivity in flexible database docking

Flexible database docking with DOCK 4.0 has been evaluated for its ability to retrieve biologically active molecules from a database of approximately 1,000 compounds with known activities against thrombin and the progesterone receptor. The retrieval of known actives and chemically similar but inactive molecules was monitored as a function of conformational and orientational sampling. The largest enrichment of actives among the 10% highest ranking molecules is obtained when only five conformations are used to seed the next round of ligand reconstruction and limited sampling is applied to place the base fragment in the binding site. The performance of energy and chemical scoring, as implemented in DOCK 4.0, was found to depend on the protein used for docking. For the progesterone receptor, energy scoring yields the largest enrichments (64%) in terms of actives retrieved among the 10% top scoring molecules, while chemical scoring performs best for thrombin (94%). With the exception of the application of energy scoring to the progesterone receptor, both energy‐based scoring schemes applied in this study do not discriminate well between true actives and chemically similar but inactive compounds. In conclusion, flexible docking is able to effectively prioritize high‐throughput screening databases, using less conformational sampling than normally required for appropriate reconstruction of protein‐ligand complexes. The more subtle discrimination between chemically similar classes of active and inactive compounds remains, however, problematic. Proteins 1999:37:334–345. ©1999 Wiley‐Liss, Inc.