二酮酸类HIV-1整合酶抑制剂的定量构效关系

应用遗传函数分析法(GFA)和分子场分析法(MFA)对一系列二酮酸类整合酶抑制剂分别进行了二维和三维定量构效关系研究, 并对随机选择的5个化合物组成的测试集进行了预测, 外在预测的r2pred值分别达到0.987和0.759, 表明模型具有良好的预测能力, 同时利用药效团分析的方法, 验证了QSAR (quantitave structure-activity relationship)模型, 并概括了疏水作用对抑制剂活性的重要影响. 研究结果表明, 电性描述符(Apol)对活性有重要影响, 意味着抑制剂与金属离子的螯合作用, 同时空间和结构因素特别是疏水作用也对活性有重要作用. 利用这些规律进行了分子设计, 在理论上获得了一些具有较高抑制剂活性的新的二酮酸类衍生物, 并期待实验证实.

Quantitative Structure-Activity Relationships of HIV-1 Integrase Inhibitors of DKAs

The quantitative structure-activity relationships(QSAR)of a series of human immunodeficiency virus type 1(HIV-1)integrase inhibitors of the derivatives of diketone acids(DKAs)were investigated using genetic function approximation(GFA)and moleculor field analysis(MFA)models and then validated by F-test and predictive-ability test.The r_(pred)~2 of these two models reached 0.987 and 0.759,respectively,which demonstrated that the models had perfect predictive ability.Furthermore pharmocophore analysis was used to confirm the models and demonstrate the importance of hydrophobic interactions.Based on the above conclusions,three new molecules of DKAs with higher activity have been theoretically designed and are waiting for support from experiment.The findings in this research will give some guidance for designing novel effective HIV-1 integrase inhibitors.