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Discovery of Rho-kinase inhibitors by docking-based virtual screening
Shen M.1; Yu H.1; Li Y.1; Li P.2; Pan P.1; Zhou S.1; Zhang L.1; Li S.3; Lee S.M.-Y.3; Hou T.1,4
Source PublicationMolecular BioSystems

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. © 2013 The Royal Society of Chemistry.

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Indexed BySCI
WOS Research AreaBiochemistry & Molecular Biology
WOS SubjectBiochemistry & Molecular Biology
WOS IDWOS:000318557100043
The Source to ArticleScopus
被引频次[WOS]:41   [WOS记录]     [WOS相关记录]
Document TypeJournal article
专题Institute of Chinese Medical Sciences
Corresponding AuthorLee S.M.-Y.; Hou T.
Affiliation1.Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, China
2.Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering, and Materials Science, Soochow University, Suzhou, China
3.State Key Laboratory for Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Taipa, China
4.College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
GB/T 7714
Shen M.,Yu H.,Li Y.,et al. Discovery of Rho-kinase inhibitors by docking-based virtual screening[J]. Molecular BioSystems,2013,9(6):1511.
APA Shen M..,Yu H..,Li Y..,Li P..,Pan P..,...&Hou T..(2013).Discovery of Rho-kinase inhibitors by docking-based virtual screening.Molecular BioSystems,9(6),1511.
MLA Shen M.,et al."Discovery of Rho-kinase inhibitors by docking-based virtual screening".Molecular BioSystems 9.6(2013):1511.
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