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 class es has been used to evaluate the performance of two implementations of incr emental construction algorithms for flexible molecular docking: DOCK 4.0 an d FlexX 1.5. Both docking tools are able to dock 10-35% of our test set wit hin 2 Angstrom of their known, bound conformations using default sampling a nd scoring parameters. Although flexible docking with DOCK or FlexX is not able to reconstruct all native complexes, it does offer a significant impro vement over rigid body docking of single, rule-based conformations, which i s still often used for docking of large databases. Docking of sets of multi ple conformers of each inhibitor, obtained with a novel protocol for divers e conformer generation and selection, yielded results comparable to those o btained by flexible docking. Chemical scoring, which is an empirically modi fied force field scoring method implemented in DOCK 4.0, outperforms both i nteraction energy scoring by DOCK and the Bohm scoring function used by Fle xX in rigid and flexible docking of thrombin inhibitors. Our results indica te that for reliable docking of flexible ligands the selection of anchor fr agments, conformational sampling and currently available scoring methods st ill require improvement.