Energetic factors determining the binding of type I inhibitors to c-Met kinase： experimental studies and quantum mechanical calculations  

作　　者：Zhe YU Yu-chi MA Jing AI Dan-qi CHEN Dong-mei ZHAO Xin WANG Yue-lei CHEN Mei-yu GENG Bing XIONG Mao-sheng CHENG Jing-kang SHEN 

机构地区：[1]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2]Shenyang Pharmaceutical University, School of Pharmaceutical Engineering, Shenyang 110016, China

出　　处：《Acta Pharmacologica Sinica》2013年第11期1475-1483,共9页中国药理学报（英文版）

摘　　要：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 n-n 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.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 n-n 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.

关 键 词：receptor tyrosine kinase type I c-Met inhibitor cancer quantum chemistry protein-ligand interaction symmetry-adaptedperturbation theory （SAPT） 

分 类 号：O561.5[理学—原子与分子物理] O4-33[理学—物理]