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Design Some New Type‐I c‐met Inhibitors Based on Molecular Docking and Topomer CoMFA Research
Author(s) -
Tian Yuanxin,
Shen Yudong,
Zhang Xianzuo,
Ye Lianbao,
Li Zhonghuang,
Liu Zhong,
Zhang Jiajie,
Wu Shuguang
Publication year - 2014
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201300118
Subject(s) - docking (animal) , chemistry , stereochemistry , linker , hydrogen bond , molecular model , stacking , computational biology , molecule , computer science , biology , organic chemistry , medicine , nursing , operating system
In this paper, a specific design strategy targeting c‐met kinase was reported based on docking modeling and topomer comparative molecular field analysis (Topomer CoMFA). A novel U‐shape conformation which is distinct from the literature was demonstrated by molecular docking among 68 U‐shape c‐met inhibitors. According to the docking results, two Topomer CoMFA models with high predictive ability were established based on the two fragment rule. The results from both docking and topomer CoMFA showed that the π–π stacking interaction with Tyr1230 and the hydrogen bond with hinge region play an important role in inhibitory activity. Furthermore, the flexible linker and the adjacent solvent group would be favorable to stabilize the conformation and to enhance the two interactions mentioned above. Based on our patent, 14 new compounds were designed by our design strategy. The binding mode exhibited as expected and their activities were predicted by topomer CoMFA model. The preliminary biological tests showed most of them have potent activity to c‐met kinase. Our study would provide guidelines to design some new U‐shaped c‐met inhibitors with new scaffolds and optimize the current molecules.