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首页> 外文期刊>Journal of chemical information and modeling >Design of Novel Rho Kinase Inhibitors Using Energy Based Pharmacophore Modeling, Shape-Based Screening, in Silico Virtual Screening, and Biological Evaluation
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Design of Novel Rho Kinase Inhibitors Using Energy Based Pharmacophore Modeling, Shape-Based Screening, in Silico Virtual Screening, and Biological Evaluation

机译：使用基于能量的药代动力学模型，基于形状的筛选，计算机模拟虚拟筛选和生物学评估设计新型Rho激酶抑制剂

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摘要

Rho-associated protein kinase (ROCK) plays a key role in regulating a variety of cellular processes, and dysregulation of ROCK signaling or expression is implicated in numerous diseases and infections. ROCK proteins have therefore emerged as validated targets for therapeutic intervention in various pathophysiological conditions such as diabetes-related complications or hepatitis C-associated pathogenesis. In this study, we report on the design and identification of novel ROCK inhibitors utilizing energy based pharmacophores and shape-based approaches. The most potent compound 8 exhibited an IC50 value of 1.5 μM against ROCK kinase activity and inhibited methymercury-induced neurotoxicity of IMR-32 cells at GI_(50) value of 0.27 μM. Notably, differential scanning fluorometric analysis revealed that ROCK protein complexed with compound 8 with enhanced stability relative to Fasudil, a validated nanomolar range ROCK inhibitor. Furthermore, all compounds exhibited ≥96 μM CC50 (50% cytotoxicity) in Huh7 hepatoma cells, while 6 compounds displayed anti-HCV activity in HCV replicon cells. The identified lead thus constitutes a prototypical molecule for further optimization and development as anti-ROCK inhibitor.
机译：Rho相关蛋白激酶（ROCK）在调节多种细胞过程中起关键作用，ROCK信号或表达的失调与多种疾病和感染有关。因此，ROCK蛋白已成为在各种病理生理条件下（例如与糖尿病相关的并发症或与丙型肝炎相关的发病机制）进行治疗干预的有效靶标。在这项研究中，我们报告了基于能量的药效团和基于形状的方法对新型ROCK抑制剂的设计和鉴定。最有效的化合物8对ROCK激酶的活性表现为1.5μM的IC50值，在GI_（50）值为0.27μM时抑制了甲基汞诱导的IMR-32细胞的神经毒性。值得注意的是，差示扫描荧光分析表明，相对于Fasudil（一种经过验证的纳摩尔范围的ROCK抑制剂），ROCK蛋白与化合物8的络合物具有更高的稳定性。此外，所有化合物在Huh7肝癌细胞中均显示出≥96μMCC50（50％的细胞毒性），而6种化合物在HCV复制子细胞中显示出抗HCV活性。因此，鉴定出的铅构成了原型分子，可以进一步优化和开发作为抗ROCK抑制剂。

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