Cui Jiaxin, Ding Mei, Deng Wei, Yin Yan, Wang Zhonghua, Zhou Hong, Sun Guofeng, Jiang Yu, Feng Yangbo
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.
Bioorg Med Chem. 2015 Dec 1;23(23):7464-77. doi: 10.1016/j.bmc.2015.10.041. Epub 2015 Oct 30.
Lim kinase (Limk), a proline/serine-rich sequence, can regulate the polymerization of the actin filaments by phosphorylating, and it is found to be highly involved in various human diseases. In this paper, 47 reported Limk1 inhibitors with bis-aryl urea scaffold were used to design potent and selective Limk inhibitors by computational approaches. Firstly, the structure-Limk1 activity relationship models (3D-QSAR) and structure-Limk1/ROCK2 selectivity relationship models (3D-QSSR) were developed and both 3D-QSAR and 3D-QSSR models showed good correlative and predictive abilities. Then, the molecular docking and molecular dynamics (MD) simulations were employed to validate the optimal docking conformation and explore the binding affinities. Finally, five new compounds were designed and all of them exhibited good Limk1 inhibition and Limk1/ROCK2 selectivity after synthesis and biological evaluation, which demonstrated that the obtained information from computational studies were valuable to guide Limk inhibitors' design.
LIM激酶（Limk）富含脯氨酸/丝氨酸序列，可通过磷酸化作用调节肌动蛋白丝的聚合，并且发现它与多种人类疾病密切相关。本文利用47种已报道的具有双芳基脲支架的Limk1抑制剂，通过计算方法设计高效且具选择性的Limk抑制剂。首先，构建了结构-Limk1活性关系模型（3D-QSAR）和结构-Limk1/ROCK2选择性关系模型（3D-QSSR），3D-QSAR和3D-QSSR模型均显示出良好的相关性和预测能力。然后，采用分子对接和分子动力学（MD）模拟来验证最佳对接构象并探究结合亲和力。最后，设计了5种新化合物，经合成及生物学评估，所有化合物均表现出良好的Limk1抑制作用和Limk1/ROCK2选择性，这表明从计算研究中获得的信息对指导Limk抑制剂的设计具有重要价值。
