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.
Acta Pharmacol Sin. 2013 Nov;34(11):1475-83. doi: 10.1038/aps.2013.85. Epub 2013 Sep 23.
To decipher the molecular interactions between c-Met and its type I inhibitors and to facilitate the design of novel c-Met inhibitors.
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.
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.
The theoretical studies have elucidated the determinant factors involved in the binding of type I inhibitors to c-Met.
解析 c-Met 与其 I 型抑制剂之间的分子相互作用，以促进新型 c-Met 抑制剂的设计。
基于原型模型抑制剂 1，合成了四个在融合芳环上略有差异的配体。采用量子化学计算每个配体的结合自由能。采用对称自适应微扰理论（SAPT）将结合能分解为几种基本力，以阐明决定因素。
量子化学计算得到的结合自由能与实验数据具有良好的相关性。SAPT 计算表明，结合的主要驱动力来自于与 Tyr-1230 的三明治π-π 相互作用。Arg-1208 是区分因素，通过骨架羰基与融合芳环系统的 6 位相互作用，其力模式类似于氢键。因此，6 位必须连接一个氢原子，而将碳原子改为氮原子会引起不利的静电相互作用。
理论研究阐明了 I 型抑制剂与 c-Met 结合的决定因素。
