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Energetic factors determining the binding of type I inhibitors to c-Met kinase: experimental studies and quantum mechanical calculations
Alternative TitleEnergetic 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 PublicationACTA PHARMACOLOGICA SINICA
ISSN1671-4083
Volume34Issue:11Pages:1475-1483
AbstractAim: To decipher the molecular interactions between c-Met and its type I inhibitors and to facilitate the design of novel c-Met inhibitors.
Other AbstractAim: 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.
KeywordSULFUR-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 ByCSCD
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 IDCSCD:4966502
Citation statistics
Cited Times:2[CSCD]   [CSCD Record]
Document Type期刊论文
Identifierhttp://ir.imr.ac.cn/handle/321006/151023
Collection中国科学院金属研究所
Affiliation1.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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