Recovery after ischemic stroke is slow and highly variable. Activated ROCK (Rho-associated coiled-coil kinase) pathway hampers recovery of impaired neurons. Though inhibiting ROCK pathway has shown therapeutic effects in vitro, the selectivity of most of the ROCK inhibitors is still not investigated. Present study aims to investigate the binding affinity in silico of nine widely used ROCK inhibitors with brain-specific ROCK2 isoform. Three-dimensional structures of ROCK2 and eight drugs were taken from Protein Data Bank and PubChem Chemical Compound Database, respectively, whereas, FSD-C10 structure was generated based on Xin et al., 2015. In docking, ROCK2 was set to be rigid and drugs were free to rotate. All simulations were carried out using AutoDock 4.2. This study demonstrated strong complexation between all ligands and ROCK2. All ROCK inhibitors, except FSD-C10, were able to bind to ROCK2 more strongly [Binding constant (K_a) between 2.6 – 36.7 × 10⁵ M⁻¹] than fasudil (Ka = 2.5 × 10⁵ M⁻¹). SLx-2119 (KD-025) had the highest binding constant (K_a = 36.7 × 10⁵ M⁻¹) thus succeeding as a better ROCK2 specific inhibitor. Selectivity of ROCK inhibitors (in silico) towards ROCK2 can be an indicative measure to estimate therapeutic benefits or adverse effects prior to in vitro study.

中文翻译：

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使用广泛使用的抑制剂靶向ROCK2亚型，以更快地恢复卒中后

缺血性中风后的恢复缓慢且变化很大。激活的ROCK（Rho相关的螺旋线圈激酶）通路阻碍受损神经元的恢复。尽管抑制ROCK途径在体外已显示出治疗作用，但大多数ROCK抑制剂的选择性仍未研究。本研究旨在研究九种广泛使用的ROCK抑制剂与脑特异性ROCK2亚型在计算机上的结合亲和力 。ROCK2和八种药物的三维结构分别来自蛋白质数据库和PubChem化学化合物数据库，而FSD-C10结构是根据Xin等人的方法生成的，2015年。在对接中，ROCK2设置为刚性，毒品可以自由旋转。所有模拟都是使用AutoDock 4.2进行的。这项研究证明了所有配体与ROCK2之间的强络合作用。所有ROCK抑制剂，除FSD-C10，[结合常数（K能够结合到ROCK2更强烈_一个2.6之间） - 36.7×10 ⁵中号^-1 ]比法舒地尔（KA = 2.5×10 ⁵中号^-1）。SLx-2119（KD-025）具有最高的结合常数（K _a = 36.7×10 ⁵ M ^-1），因此成功作为更好的ROCK2特异性抑制剂。ROCK抑制剂的选择性（在硅片）对ROCK2可能是在进行体外研究之前评估治疗益处或不良反应的指示性措施。