title: Importance of consensus region of multiple-ligand templates in a virtual screening method.
abstract: We discuss methods and ideas of virtual screening (VS) for drug discovery by examining the performance of VS-APPLE, a recently developed VS method, which extensively utilizes the tendency of single binding pockets to bind diversely different ligands,i.e.promiscuity of binding pockets. In VS-APPLE, multiple ligands bound to a pocket are spatially arranged by maximizing structural overlap of the protein while keeping their relative position and orientation with respect to the pocket surface, which are then combined into a multiple-ligand template for screening test compounds. To greatly reduce the computational cost, comparison of test compound structures are made only with limited regions of the multiple-ligand template. Even when we use the narrow regions with most densely populated atoms for the comparison, VSAPPLE outperforms other conventional VS methods in terms of Area Under the Curve (AUC) measure. This region with densely populated atoms corresponds to the consensus region among multiple ligands. It is typically observed that expansion of the sampled region including more atoms improves screening efficiency. However, for some target proteins, considering only a small consensus region is enough for the effective screening of test compounds. These results suggest that the performance test of VS methods sheds light on the mechanisms of protein-ligand interactions, and elucidation of the protein-ligand interactions should further help improvement of VS methods.
authors.affiliation: Department of Applied Physics, Nagoya University, Nagoya, Aichi 464-8603, Japan; Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Okuno
authors.affiliation: Department of Computational Science and Engineering, Nagoya University, Nagoya, Aichi 464-8603, Japan.
authors.forename: Koya
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Complex Systems Science, Nagoya University, Nagoya, Aichi 464-8601, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Minami
authors.affiliation: Department of Computational Science and Engineering, Nagoya University, Nagoya, Aichi 464-8603, Japan.
authors.forename: Tomoki P
authors.initials: TP
authors.lastname: Terada
authors.affiliation: Department of Computational Science and Engineering, Nagoya University, Nagoya, Aichi 464-8603, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Sasai
authors.affiliation: Department of Computational Science and Engineering, Nagoya University, Nagoya, Aichi 464-8603, Japan.
authors.forename: George
authors.initials: G
authors.lastname: Chikenji
keywords: computational speed; drug discovery; flexibility; promiscuity