2,6,9-三取代嘌呤衍生物三维定量构效关系和靶点相互作用

Three-dimensional quantitative structure-activity relationships and interactions with targets of 2,6,9,-substituted purine derivatives

采用易位体比较分子场(Topomer CoMFA)法研究2,6,9-三取代嘌呤类衍生物的三维定量构效(3D-QSAR)关系,将45个化合物随机分为训练集和测试集,以电性参数和立体参数为自变量,pIC 50为因变量,采用偏最小二乘法进行模型拟合,抽一法交互验证检验模型的内部预测能力,测试集验证模型的外部预测能力,所得优化模型的F检验值、拟合、交互验证及外部验证系数分别为100.35,0.954,0.929,0.566。通过Surflex-dock分子对接研究嘌呤类衍生物与CDK2的作用模式,3D-QSAR模型和分子对接结果表明,嘌呤6位宜引入较大体积,2位宜引入负电性取代基,9位宜取代长碳链基团。

Three-dimensional quantitative structure-activity relationships(3D-QSAR)of 2,6,9,-substituted purine derivatives were by Topomer CoMFA.Forty-five compounds were randomly divided into training set and test set.The model was established by partial least squares method based on electrical and stereo parameters as independent variables,pIC 50 as dependent variables.The internal prediction ability of the model was verified by Leave-One-Out and the external prediction ability was verified by the test set.The F test values,fitting,interactive verification and external verification coefficients of the resulting optimization model are 100.35,0.954,0.929,0.566,respectively.The interactions of purine derivatives and CDK2 were studied by Surflex-dock molecular docking.Combined with the results of 3D-QSAR and molecular docking,the substituents forming hydrogen bonds can be introduced to 6position,the negative substituents be introduced to 2position and the long carbon chain group can be introduced to 9sites in purine.