Discovery of Rho-kinase inhibitors by docking-based virtual screening

Mingyun Shen; Huidong Yu; Youyong Li; Pixu Li; Peichen Pan; Shunye Zhou; Liling Zhang; Shang Li; Simon Ming-Yuen Lee; Tingjun Hou

doi:10.1039/C3MB00016H

Discovery of Rho-kinase inhibitors by docking-based virtual screening†

Mingyun Shen,^a Huidong Yu,^a Youyong Li,^a Pixu Li,^b Peichen Pan,^a Shunye Zhou,^a Liling Zhang,^a Shang Li,^c Simon Ming-Yuen Lee*^c and Tingjun Hou*^ad

Author affiliations

* Corresponding authors

^a Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China
E-mail: tingjunhou@hotmail.com
Tel: +86-512-65882039

^b Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering, and Materials Science, Soochow University, Suzhou, Jiangsu 215123, China

^c State Key Laboratory for Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Taipa, China
E-mail: simonlee@umac.mo
Tel: +853-8397-4695

^d College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China

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.

Molecular BioSystems

Discovery of Rho-kinase inhibitors by docking-based virtual screening†

Abstract

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Discovery of Rho-kinase inhibitors by docking-based virtual screening

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