基于吲哚类的ROCK激酶抑制剂定量构效关系的研究  

Study on quantitative structure-activity relationship of Indole derivativesas rho kinase(ROCK) inhibitors

作　　者：肖元春[1] 李燕[1] 杨银凤[1] 王景辉[1] 杨凌[2] 

机构地区：[1]大连理工大学化工学院,辽宁大连116024 [2]中国科学院大连化学物理研究所药物资源开发研究组,辽宁大连116023

出　　处：《分子科学学报》2015年第4期295-303,共9页Journal of Molecular Science

基　　金：国家自然科学基金资助项目(11201049)

摘　　要：基于计算生物学方法对61个ROCK激酶靶标分子建立三维定量构效关系(3DQSAR)模型.在基于配体叠合的基础上,发现CoMSIA中2个场组合(位阻场和疏水场)为最好的模型(Q2=0.509,R2ncv=0.987,SEE=0.131,F=287.999和R2pre=0.837).基于此模型基础上的三维等势线图形象地说明了在各个位置增加疏水性的大取代基或者亲水性基团有利于提高分子的生物活性.此外,分子对接模拟结果显示了氨基酸Glu170,Met172和Asp232在受体调节剂中发挥着重要作用.这些结果能够帮助深入了解ROCK激酶的作用机理,并且能够为今后的药物设计提供新的方向.For the first time,via comparative molecular field analysis（CoMFA）and comparative molecular similarity indices analysis（CoMSIA）,a set of ligand-and receptor-based 3D-QSAR models were carried out to explore the structure-activity correlation of 61 ROCK promising inhibitors.Based on the ligand-based alignment,an optimal CoMSIA model（SH）was obtained with good predictive power of Q2=0.509,R2ncv=0.987,SEE=0.131,F=287.999 and R2pred=0.837.The 3Dcontour maps suggested that the compounds substituted on special position with bulky hydrophobic or hydrophilic groups can enhance the biological activity.Furthermore,the docking analysis showed that Glu170,Met172 and Asp232which formed three H-bonds are crucial for ROCK receptor.The present work provides useful guidelines for future structural modifications of this class of compounds,which would assist the development of superior ROCK inhibitors.

关 键 词：ROCK激酶抑制剂 比较分子力场 比较相似性指数分析 分子对接 

分 类 号：O641[理学—物理化学]