VEGFR2活性腔性质以及与抑制剂的结合模式研究

VEGFR2介导肿瘤诱导的血管生成作用, 是抑制肿瘤生长和转移的新靶点. 为深入探讨VEGFR2活性腔性质以及与抑制剂的结合模式, 采用多拷贝同时搜寻法(MCSS)研究VEGFR2活性腔的性质, 然后用分子对接方法对5个已上临床的VEGFR抑制剂与VEGFR2活性腔进行对接计算, 讨论它们的结合模式, 确定与配体结合相关的关键残基. 研究发现: 疏水腔I, II是配体结合的关键区域, 残基Glu915, Cys917是关键的氢键作用位点, Lys866, Glu883和Asp1044形成的极性区域对提高配体亲合力很重要, 疏水腔III和极性腔IV是额外增强配体结合力的区域, IV区的Arg1030可提供额外的氢键作用位点. 本研究可为全新VEGFR2抑制剂的合理药物设计提供理论依据, 为寻找新的抗肿瘤药物奠定基础.

Study of Properties of VEGFR2 Active Site and Binding Mode of VEGFR2 and Its Inhibitors

VEGFR2, which plays crucial roles in angiogenesis induced by tumor, is a new ideal target for inhibiting development and metastasis of tumor. To study the properties of VEGFR2 active site and binding mode of VEGFR2 and its inhibitors, MCSS (Multiple Copy Simultaneous Search) method was applied to explore properties of active site of VEGFR2. Then five inhibitors which are under clinical trial evaluations were docked into the active site of VEGFR2 to study the mode of interaction and to determine the critical residues involved in binding. It was found that hydrophobic pockets I and II are crucial for inhibitors’ binding. Glu915 and Cys917 residues are crucial hydrogen bond acceptor and donor respectively. A polar zone formed by Lys866, Glu883 and Asp1044 is important for ligands’ binding. Hydrophobic pocket III and polar pocket IV enhance binding affinity additionally. Arg1030 residue serves as an additional hydrogen bond donor. These results provide a basis for rational design of novel potent VEGFR2 inhibitors and for discovery of new anticancer drugs.