title: Discovery of Rho-kinase inhibitors by docking-based virtual screening.
abstract: Rho kinases (ROCK1 and ROCK2) belong to serine/threonine (Ser/Thr) protein kinase family, and play the central roles in the organization of the actin cytoskeleton. Therefore, Rho kinases have become attractive targets for the treatments of many diseases, such as cancer, renal disease, hypertension, ischemia, and stroke. In order to develop small-molecule inhibitors of ROCK1, molecular docking was utilized to virtually screen two chemical databases and identify molecules that interact with ROCK1. A small set of virtual hits was purchased and submitted to a series of experimental assays. The in vitro enzyme-based and cell-based assays reveal that 12 compounds have good inhibitory activity against ROCK1 in the micro molar regime (IC50 values between about 7 and 28 μM) and antitumor activity against lung cancer, breast cancer or/and myeloma cell lines. The structural analysis shows that two active compounds present novel scaffolds and are potential leads for the development of novel anti-cancer drugs. We then characterized the interaction patterns between ROCK1 and two inhibitors with novel scaffolds by molecular dynamics (MD) simulations and free energy decomposition analysis. In addition, the pharmacological effect of the two ROCK1 inhibitors with novel scaffolds on atorvastatin-induced cerebral hemorrhage was evaluated by using zebrafish model, and one compound candidate is able to prevent atorvastatin-induced cerebral hemorrhage effectively.
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: Mingyun
authors.initials: M
authors.lastname: Shen
authors.forename: Huidong
authors.initials: H
authors.lastname: Yu
authors.forename: Youyong
authors.initials: Y
authors.lastname: Li
authors.forename: Pixu
authors.initials: P
authors.lastname: Li
authors.forename: Peichen
authors.initials: P
authors.lastname: Pan
authors.forename: Shunye
authors.initials: S
authors.lastname: Zhou
authors.forename: Liling
authors.initials: L
authors.lastname: Zhang
authors.forename: Shang
authors.initials: S
authors.lastname: Li
authors.forename: Simon Ming-Yuen
authors.initials: SM
authors.lastname: Lee
authors.forename: Tingjun
authors.initials: T
authors.lastname: Hou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000069059:Atorvastatin; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006367:HeLa Cells; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D015027:Zebrafish; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006538:Heptanoic Acids; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases