Energetic factors determining the binding of type I inhibitors to c-Met kinase: experimental studies and quantum mechanical calculations | |
Alternative Title | Energetic factors determining the binding of type I inhibitors to c-Met kinase: experimental studies and quantum mechanical calculations |
Yu Zhe1; Ma Yuchi1; Ai Jing1; Chen Danqi1; Zhao Dongmei2; Wang Xin1; Chen Yuelei1; Geng Meiyu1; Xiong Bing1; Cheng Maosheng2; Shen Jingkang1 | |
2013 | |
Source Publication | ACTA PHARMACOLOGICA SINICA
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ISSN | 1671-4083 |
Volume | 34Issue:11Pages:1475-1483 |
Abstract | Aim: To decipher the molecular interactions between c-Met and its type I inhibitors and to facilitate the design of novel c-Met inhibitors. |
Other Abstract | Aim: To decipher the molecular interactions between c-Met and its type I inhibitors and to facilitate the design of novel c-Met inhibitors. Methods: Based on the prototype model inhibitor 1, four ligands with subtle differences in the fused aromatic rings were synthesized. Quantum chemistry was employed to calculate the binding free energy for each ligand. Symmetry-adapted perturbation theory (SAPT) was used to decompose the binding energy into several fundamental forces to elucidate the determinant factors. Results: Binding free energies calculated from quantum chemistry were correlated well with experimental data. SAPT calculations showed that the predominant driving force for binding was derived from a sandwich π–π interaction with Tyr-1230. Arg-1208 was the differentiating factor, interacting with the 6-position of the fused aromatic ring system through the backbone carbonyl with a force pattern similar to hydrogen bonding. Therefore, a hydrogen atom must be attached at the 6-position, and changing the carbon atom to nitrogen caused unfavorable electrostatic interactions. Conclusion: The theoretical studies have elucidated the determinant factors involved in the binding of type I inhibitors to c-Met. |
Keyword | SULFUR-PI INTERACTIONS PERTURBATION-THEORY SUBSTITUENTS SANDWICH BENZENE PATHWAY receptor tyrosine kinase type I c-Met inhibitor cancer quantum chemistry protein-ligand interaction symmetry-adapted perturbation theory (SAPT) |
Indexed By | CSCD |
Language | 英语 |
Funding Project | [Program of Excellent Young Scientists of the Chinese Academy of Sciences] ; [National Natural Science Foundation of China] ; ["Interdisciplinary Cooperation Team" Program for Science and Technology Innovation of the Chinese Academy of Sciences] |
CSCD ID | CSCD:4966502 |
Citation statistics |
Cited Times:2[CSCD]
[CSCD Record]
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Document Type | 期刊论文 |
Identifier | http://ir.imr.ac.cn/handle/321006/151026 |
Collection | 中国科学院金属研究所 |
Affiliation | 1.中国科学院 2.中国科学院金属研究所 |
Recommended Citation GB/T 7714 | Yu Zhe,Ma Yuchi,Ai Jing,et al. Energetic factors determining the binding of type I inhibitors to c-Met kinase: experimental studies and quantum mechanical calculations[J]. ACTA PHARMACOLOGICA SINICA,2013,34(11):1475-1483. |
APA | Yu Zhe.,Ma Yuchi.,Ai Jing.,Chen Danqi.,Zhao Dongmei.,...&Shen Jingkang.(2013).Energetic factors determining the binding of type I inhibitors to c-Met kinase: experimental studies and quantum mechanical calculations.ACTA PHARMACOLOGICA SINICA,34(11),1475-1483. |
MLA | Yu Zhe,et al."Energetic factors determining the binding of type I inhibitors to c-Met kinase: experimental studies and quantum mechanical calculations".ACTA PHARMACOLOGICA SINICA 34.11(2013):1475-1483. |
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