title: Optimization of high throughput virtual screening by combining shape-matching and docking methods.
abstract: Receptor flexibility is a critical issue in structure-based virtual screening methods. Although a multiple-receptor conformation docking is an efficient way to account for receptor flexibility, it is still too slow for large molecular libraries. It was reported that a fast ligand-centric, shape-based virtual screening was more consistent for hit enrichment than a typical single-receptor conformation docking. Thus, we designed a "distributed docking" method that improves virtual high throughput screening by combining a shape-matching method with a multiple-receptor conformation docking. Database compounds are classified in advance based on shape similarities to one of the crystal ligands complexed with the target protein. This classification enables us to pick the appropriate receptor conformation for a single-receptor conformation docking of a given compound, thereby avoiding time-consuming multiple docking. In particular, this approach utilizes cross-docking scores of known ligands to all available receptor structures in order to optimize the algorithm. The present virtual screening method was tested for reidentification of known PPARgamma and p38 MAP kinase active compounds. We demonstrate that this method improves the enrichment while maintaining the computation speed of a typical single-receptor conformation docking.
authors.affiliation: Department of Biological Sciences, Research Center for Women's Diseases (RCWD), Sookmyung Women's University, Hyochangwongil 52, Yongsan-gu, Seoul, Republic of Korea 140-742.
authors.forename: Hui Sun
authors.initials: HS
authors.lastname: Lee
authors.forename: Jiwon
authors.initials: J
authors.lastname: Choi
authors.forename: Irina
authors.initials: I
authors.lastname: Kufareva
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Anton
authors.initials: A
authors.lastname: Filikov
authors.forename: Young
authors.initials: Y
authors.lastname: Yang
authors.forename: Sukjoon
authors.initials: S
authors.lastname: Yoon
mesh_terms: D004353:Drug Evaluation, Preclinical; D015394:Molecular Structure; D011956:Receptors, Cell Surface / Q000737:chemistry
chemical_list: D011956:Receptors, Cell Surface