BEAR, a novel virtual screening methodology based on molecular dynamics refinement and accurate binding free Energy estimation.

The method, named BEAR (Binding Estimation After Refinement), is a new automated post-docking procedure based on the conformational refinement of docking poses through molecular dynamics (MD) followed by accurate predictions of protein binding free energies using MM-PBSA and MM-GBSA. When applied to a huge virtual screening campaign aimed at identifying new Plasmodium falciparum plasmepsin inhibitors, BEAR discovered 26 novel and potent (nM) inhibitors out of the 30 compounds tested in the wet lab, thereby giving an impressive hit rate.5 Importantly, BEAR allowed the discovery of two entirely new classes of inhibitors. These evidences strongly confirmed the potential of our virtual screening procedure for drug discovery. BEAR post-processing yielded strikingly better enrichment factors than those obtained with docking, and demonstrated to be a reliable tool for drug discovery. The BEAR scoring functions resulted reliable and able to recognize and to discriminate known ligands among compounds with unknown activity.