中文摘要：

目的研究二酮酸类化合物（diketoacids，DKAs）与HIV-1整合酶（integrase，IN）的分子识别机制和二者复合物的构象变化，为预测同类化合物抑制活性提供理论支持。方法使用AutoDock程序包将10个二酮酸类化合物与整合酶进行了分子对接，得到一系列对接复合物模型。选取其中两个抑制活性有明显差异的复合物进行了15ns的分子动力学模拟，并从能量和氢键的角度分析了二者与HIV-1整合酶识别的关键残基。结果二者特异性识别主要依靠与DDE基序形成的氢键，结合在由1141～M154，W61-L63和V77构成的口袋中，与实验数据吻合。基于分子动力学模拟轨迹做了结合自由能分解，其中范德华能项与IgIC50有较高的线性相关，结果表明该方程可用于此类化合物的活性预测。结论氢键是抑制剂维持活性及复合物稳定的重要作用力。结合自由能中的疏水作用与抑制活性有明确的相关性。对后续HIV-1整合酶抑制剂设计具有一定的指导意义。

英文摘要：

Objective To investigate molecular recognition mechanism between diketoacids （DKAs） and HIV- 1 integrase （IN） and conformational change of IN after binding with DKAs, facilitate prediction of the inhibitory activity of similar compounds and establishment of a theoretical foundation. Methods Autodock software was used to perform molecular docking between 10 DKAs and IN and a series of docking complex models were gained. Two 15ns molecular dynamics simulations were performed for two complex with significantly different inhibitory activity. The key residues that enable IN to recognize DKAs were analyzed analyzing energy and hydrogen bond information. Results The specific recognition between DKAs and IN is mainly dependent on the hydrogen bond formed by DDE motif. The binding pocket is mainly composed with I141-M154, W61-L63 and V77, which is consistent with the previous experiment data. Binding free energy was decomposed based on molecular dynamics simulation trajectory, where van der Waals and IgIC50 have relatively high linear correlation. The results show that the equation can be used to predict the activity of this type of compounds. Conclusion Hydrogen bond is an important binding force for maintaining inhibitory activity of DKAs and IN-DKAs complex stability. Hydrophobic past in binding free energy has a great correlation with inhibitory activity, which provides some certain guidance meaning for the subsequent anti- IN inhibitor design.