The c-Met tyrosine kinase plays an important role in human cancers. Preclinical studies demonstrated that c-Met is over-expressed, mutated and amplified in a variety of human tumor types and design of more potent c-Met inhibitors is a priority. In this study, 14 molecular dynamics simulations of potent type II c-Met inhibitors were run to resolve the critical interactions responsible for high affinity of ligands towards c-Met considering the essential flexibility of protein–ligand interactions. Residues Phe1223 and Tyr1159, involved in pi-pi interactions were recognized as the most effective residues in the ligand binding in terms of binding free energies. Hydrogen bond interaction with Met1160 was also found necessary for effective type II ligand binding to c-Met.

Graphic abstract

中文翻译：

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II型c-Met抑制剂：分子洞察有效抑制的关键相互作用

c-Met 酪氨酸激酶在人类癌症中起重要作用。临床前研究表明，c-Met 在多种人类肿瘤类型中过度表达、突变和扩增，设计更有效的 c-Met 抑制剂是当务之急。在这项研究中，考虑到蛋白质-配体相互作用的基本灵活性，对有效的 II 型 c-Met 抑制剂进行了 14 次分子动力学模拟，以解决导致配体对 c-Met 高亲和力的关键相互作用。就结合自由能而言，参与 pi-pi 相互作用的残基 Phe1223 和 Tyr1159 被认为是配体结合中最有效的残基。还发现与 Met1160 的氢键相互作用对于有效地与 c-Met 结合的 II 型配体是必需的。

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