Comparison of two implementations of the incremental construction algorithm in flexible docking of thrombin inhibitors

A set of 32 known thrombin inhibitors representing different chemical classes has been used to evaluate the performance of two implementations of incremental construction algorithms for flexible molecular docking: DOCK 4.0 and FlexX 1.5. Both docking tools are able to dock 10–35% of our test set within 2 Å of their known, bound conformations using default sampling and scoring parameters. Although flexible docking with DOCK or FlexX is not able to reconstruct all native complexes, it does offer a significant improvement over rigid body docking of single, rule-based conformations, which is still often used for docking of large databases. Docking of sets of multiple conformers of each inhibitor, obtained with a novel protocol for diverse conformer generation and selection, yielded results comparable to those obtained by flexible docking. Chemical scoring, which is an empirically modified force field scoring method implemented in DOCK 4.0, outperforms both interaction energy scoring by DOCK and the Böhm scoring function used by FlexX in rigid and flexible docking of thrombin inhibitors. Our results indicate that for reliable docking of flexible ligands the selection of anchor fragments, conformational sampling and currently available scoring methods still require improvement.