强效且选择性的基于尿素的ROCK抑制剂的发现：通过三维定量构效关系、分子对接和分子动力学模拟探索抑制剂的效力及ROCK2/PKA选择性
Discovery of potent and selective urea-based ROCK inhibitors: Exploring the inhibitor's potency and ROCK2/PKA selectivity by 3D-QSAR, molecular docking and molecular dynamics simulations.
作者信息
Mei Ding, Yin Yan, Wu Fanhong, Cui Jiaxing, Zhou Hong, Sun Guofeng, Jiang Yu, Feng Yangbo
机构信息
School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd., Shanghai 201418, PR China.
School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd., Shanghai 201418, PR China; Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling Ling Rd., Shanghai 200032, PR China.
出版信息
Bioorg Med Chem. 2015 May 15;23(10):2505-17. doi: 10.1016/j.bmc.2015.03.047. Epub 2015 Mar 25.
An activity model and a selectivity model from 3D-QSAR studies were established by CoMFA and CoMSIA to explore the SAR. Then docking was used to study the binding modes between ligand and kinases (ROCK2 and PKA), and the molecular docking results were further validated by MD simulations. Computational results suggested that substitution containing positive charge attached to the middle phenyl ring, or electropositive group in urea linker was favored for both activity and ROCK2/PKA selectivity. Finally, three compounds were designed, and biological evaluation demonstrated that these molecular models were effective for guiding the design of potent and selective ROCK inhibitors.
通过比较分子场分析法（CoMFA）和比较分子相似性指数分析法（CoMSIA）建立了三维定量构效关系（3D-QSAR）研究的活性模型和选择性模型，以探索构效关系（SAR）。然后采用对接方法研究配体与激酶（ROCK2和PKA）之间的结合模式，并通过分子动力学（MD）模拟进一步验证分子对接结果。计算结果表明，连接在中间苯环上带有正电荷的取代基或脲连接体中的电正性基团有利于活性和ROCK2/PKA选择性。最后，设计了三种化合物，生物学评价表明这些分子模型对于指导高效和选择性ROCK抑制剂的设计是有效的。
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