Molecular Modeling of Exquisitely Selective c-Met Inhibitors through 3D-QSAR and Molecular Dynamics Simulations
Molecular Modeling of Exquisitely Selective c-Met Inhibitors through 3D-QSAR and Molecular Dynamics Simulations
复制标题
通过 3D-QSAR 和分子动力学模拟对精细选择性 c-Met 抑制剂进行分子建模
DOI：
10.1021/ci500268s
复制
发表时间：
2014-09
影响因子：
5.6
通讯作者：
Lu Tao
中科院分区：
文献类型：
--
作者：
Yuan Haoliang;Zhuang Jin;Hu Shihe;Li Huifang;Xu Jinxing;Hu Yaning;Xiong Xiao;Chen Yadong;Lu Tao
c-Met已被认为是开发抗肿瘤药物的有吸引力的靶点。高选择性的c-Met抑制剂为安全地与其他疗法组合以实现最佳疗效提供了宝贵的机会。本工作采用分子对接、三维定量构效关系（3D-QSAR）和分子动力学模拟相结合的方法，对一系列具有精细选择性的三唑并吡嗪类c-Met抑制剂进行了研究。比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）模型的开发，以揭示c-Met抑制的结构决定因素。两种模型均被验证具有较高的可靠性和可预测性，等高线图分析表明了支架上不同取代基的特征要求。值得注意的是，在独特的窄通道中鉴定了一个重要的富含氢键的区域，这与其他激酶不同。分子动力学模拟和结合自由能的计算进一步支持了在这个富含氢键的区域中合适的基团对配体的结合做出了巨大的贡献。此外，与窄通道残基的氢键也被表明是必不可少的，以提高活性和选择性。本研究将有助于发现和优化具有更高活性和选择性的新型c-Met抑制剂。
c-Met has been considered as an attractive target for developing antitumor agents. The highly selective c-Met inhibitors provide invaluable opportunities for the combination with other therapies safely to achieve the optimal efficacy. In this work, a series of triazolopyrazine c-Met inhibitors with exquisitely selectivity were investigated using a combination of molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR), and molecular dynamics simulation. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models were developed to reveal the structural determinants for c-Met inhibition. Both models were validated to have high reliability and predictability, and contour map analysis suggested feature requirements for different substituents on the scaffold. It is worth noting that an important hydrogen bond rich region was identified in the unique narrow channel, which is distinct from other kinases. Molecular dynamics simulations and binding free energy calculations provided further support that suitable groups in this hydrogen bond rich region made great contributions to the binding of ligands. Moreover, hydrogen bonds with residues of the narrow channel were also indicated to be essential to improve the activity and selectivity. This study will facilitate the discovery and optimization of novel c-Met inhibitors with higher activity and selectivity.
登录
查看更多内容
影响因子：
3.8
作者：
Yanmin Zhang;Haichun Liu;Yu Jiao;H. Yuan;Fengxiao Wang;Shuai Lu;Sihui Yao;Zhipeng Ke;Wenting Tai;Yulei Jiang;Yadong Chen;T. Lu
通讯作者：
Yanmin Zhang;Haichun Liu;Yu Jiao;H. Yuan;Fengxiao Wang;Shuai Lu;Sihui Yao;Zhipeng Ke;Wenting Tai;Yulei Jiang;Yadong Chen;T. Lu
影响因子：
7.3
作者：
Cui, J. Jean;McTigue, Michele;Christensen, James
通讯作者：
Christensen, James
影响因子：
7.3
作者：
Kontoyianni, M;McClellan, LM;Sokol, GS
通讯作者：
Sokol, GS
影响因子：
3.4
作者：
Fang Chen;Ying Wang;Jing Ai;Zhengsheng Zhan;Yongcong Lv;Zhongjie Liang;C. Luo;De-sheng Mei;M. Geng;W. Duan
通讯作者：
Fang Chen;Ying Wang;Jing Ai;Zhengsheng Zhan;Yongcong Lv;Zhongjie Liang;C. Luo;De-sheng Mei;M. Geng;W. Duan
影响因子：
64.8
作者：
Straussman, Ravid;Morikawa, Teppei;Shee, Kevin;Barzily-Rokni, Michal;Qian, Zhi Rong;Du, Jinyan;Davis, Ashli;Mongare, Margaret M.;Gould, Joshua;Frederick, Dennie T.;Cooper, Zachary A.;Chapman, Paul B.;Solit, David B.;Ribas, Antoni;Lo, Roger S.;Flaherty, Keith T.;Ogino, Shuji;Wargo, Jennifer A.;Golub, Todd R.
通讯作者：
Golub, Todd R.