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目的构建血管内皮细胞生长因子受体2(VEGFR-2)抑制剂的三维药效团模型,为设计新型抑制剂建立理论模型。方法应用Discovery Studio 2.5中的Catalyst模块,选取已确证结合于VEGFR-2活性腔、结合模式一致、抑制活性跨度5个数量级、结构具有多样性的30个抑制剂,其中21个分子作为训练集,余9个分子作为测试集产生三维药效团模型。结果最优药效团模型由1个氢键受体、2个疏水中心、1个芳环平面和4个排斥体积组成,预测相关性R为0.89。结论交叉验证结果表明药效团模型具有较好的预测能力,可用于数据库搜索筛选结构新颖的抑制VEGFR-2的先导化合物。
Objective To construct a three-dimensional pharmacophore model of vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor and establish a theoretical model for the design of novel inhibitors. Methods Using Catalyst module in Discovery Studio 2.5, we selected 30 inhibitors that have been confirmed to bind to the active site of VEGFR-2, with a consistent pattern of binding, five orders of magnitude of inhibitory activity span, and diverse structures. 21 of them were used as training set, The remaining nine molecules served as a test set to generate a three-dimensional pharmacophore model. Results The optimal pharmacophore model consisted of one hydrogen bond acceptor, two hydrophobic centers, one aromatic ring plane and four repulsive volumes. The correlation coefficient R was 0.89. Conclusion The cross-validation results show that the pharmacophore model has good predictive ability and can be used in database search to screen for novel lead compounds that inhibit VEGFR-2.