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血管内皮生长因子VEGF及其受体VEGFR2对于肿瘤血管生成起至关重要的作用。本文旨在研究VEGFR2的咪唑并哒嗪类抑制剂的三维定量构效关系及新抑制剂分子与VEGFR2的作用机制。构建的Topomer Co MFA模型具有较强的预测能力和拟合能力(q~2=0.809,r~2=0.968)以及外部预测能力(r_(pred)~2=0.571)。应用Topomer Search技术在含1304868个分子的ZINC数据库中进行了虚拟筛选,采用基于片段的药物设计方法设计了68个高活性的新VEGFR2抑制剂。最后借助Surflex-dock技术研究了新分子与VEFGR2的作用机制,发现新抑制剂与残基Glu885、Cys919、Asn923、Asp1046等作用显著。本研究为VEGFR2抑制剂分子的结构修饰、设计与合成提供了重要的理论指导。
Vascular endothelial growth factor VEGF and its receptor VEGFR2 play an important role in tumor angiogenesis. The purpose of this paper is to investigate the three-dimensional quantitative structure-activity relationship of imidazopyridazine inhibitors of VEGFR2 and the mechanism of action of new inhibitor molecules and VEGFR2. The constructed Topomer Co MFA model has strong predictive ability and fitting ability (q ~ 2 = 0.809, r ~ 2 = 0.968) and external forecasting ability (r_ (pred) ~ 2 = 0.571). Using Topomer Search technology, we screened a total of 1,304,868 molecules in the ZINC database and designed 68 highly active new VEGFR2 inhibitors using fragment-based drug design. Finally, using Surflex-dock technology to study the mechanism of interaction between the new molecule and VEFGR2, the new inhibitor was found to have significant effects on the residues Glu885, Cys919, Asn923, Asp1046 and the like. This study provides important theoretical guidance for structural modification, design and synthesis of VEGFR2 inhibitors.