HIV-1整合酶链转移抑制剂的3D-QSAR、分子对接和分子动力学模拟研究

Study on 3D-QSAR,Molecular Docking and Molecular Dynamics of HIV-1 Integrase Chain Transfer Inhibitors

为了获得高活性、结构新颖的整合酶链转移(INST)抑制剂,本文采用Co MFA和Co MSIA两种方法对32个萘啶类INST抑制剂进行了三维定量构效关系研究,并建立了相关模型,其交叉验证系数分别为q^2=0.809和q^2=0.816,拟合验证系数分别为r^2=0.998和r^2=0.981,表明所建立的模型是可靠的且具有一定的预测能力。利用分子对接探讨小分子化合物与INST蛋白的相互作用模式,结果表明,萘啶类化合物主要通过疏水作用和氢键作用与INSTIs蛋白结合。最后通过分子动力学模拟进一步验证对接结果发现,对接的结合模式与分子动力学模拟得到的结果是一致的。本研究获得的综合模型和推论可以为开发有效的HIV INSTIs提供重要的理论信息。

In order to obtain highly active,novel integrase strand transfer inhibitors( INSTIs),threedimensional quantitative structure-activity relationship of 32 naphthyridine INST inhibitors were studied using Co MFA and Co MSIA leading to reliable models. The cross-validation coefficients were q^2= 0. 809 and q^2= 0. 816,the fitting verification coefficients were r^2= 0. 998 and r^2= 0. 981,indicating the predictive ability of the established models.Molecular docking was also performed to investigate the binding mode of small molecule compounds to INSTIs. The binding mode indicated that naphthyridines bind to INSTIs mainly via hydrophobic interactions and hydrogen bonding.Finally,the docking results were further verified by molecular dynamics simulation,and it was found that the binding mode of the docking was consistent with the results obtained by molecular dynamics simulation. The comprehensive models and inferences obtained in this study can provide an important theoretical information for the development of new and effective HIV INSTIs.