title: Development and evaluation of an integrated virtual screening strategy by combining molecular docking and pharmacophore searching based on multiple protein structures.
abstract: In this study, we developed and evaluated a novel parallel virtual screening strategy by integrating molecular docking and complex-based pharmacophore searching based on multiple protein structures. First, the capacity of molecular docking or pharmacophore searching based on any single structure from nine crystallographic structures of Rho kinase 1 (ROCK1) to distinguish the known ROCK1 inhibitors from noninhibitors was evaluated systematically. Then, the naı̈ve Bayesian classification or recursive partitioning technique was employed to integrate the predictions from molecular docking and complex-based pharmacophore searching based on multiple crystallographic structures of ROCK1, and the integrated protocol yields much better performance than molecular docking or complex-based pharmacophore searching based on any single ROCK1 structure. Finally, the well-validated integrated virtual screening protocol was applied to identify potential inhibitors of ROCK1 from traditional chinese medicine (TCM). The obtained potential active compounds from TCM are structurally novel and diverse compared with the known inhibitors of ROCK1, and they may afford valuable clues for the development of potent ROCK1 inhibitors.
authors.affiliation: Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University , Suzhou, Jiangsu 215123, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Tian
authors.forename: Huiyong
authors.initials: H
authors.lastname: Sun
authors.forename: Youyong
authors.initials: Y
authors.lastname: Li
authors.forename: Peichen
authors.initials: P
authors.lastname: Pan
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Tingjun
authors.initials: T
authors.lastname: Hou
mesh_terms: D001185:Artificial Intelligence; D001499:Bayes Theorem; D001665:Binding Sites; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004365:Drugs, Chinese Herbal / Q000737:chemistry*; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014584:User-Computer Interface; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D004365:Drugs, Chinese Herbal; D008024:Ligands; D047428:Protein Kinase Inhibitors; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases