HIV-1整合酶与芳香二酮酸类抑制剂相互作用的分子模拟研究

用分子对接方法研究了一系列芳香二酮酸类抑制剂与HIV-1整合酶的识别及相互作用. 结果表明, 抑制剂结合到整合酶Asp64～Leu68, Thr115～Phe121, Gln148～Lys159和Mg2＋所构成的口袋区, 抑制机理与5CITEP相似. 采用分子动力学模拟和MM/PBSA方法计算了芳香二酮酸类抑制剂与整合酶之间的结合自由能, 计算结果与实验值相吻合, 平均绝对偏差为3.6 kJ/mol, 体系范德华相互作用和溶剂化效应的非极性项是利于形成复合物的主要因素. 相关性分析结果表明, 结合自由能值与疏水相互作用有较强的线性相关(R＝0.61), 基于此, 用多元线性回归方法给出了一个能较强预测芳香二酮酸类抑制剂与HIV-1整合酶的结合自由能预测模型, 为后续基于抑制剂结构的抗HIV-1药物分子设计提供指导.

Study on the Interactions between HIV-1 Integrase and Aryl Diketoacid Inhibitors with Molecular Simulation Methods

The recognitions and interactions of a series of aryl diketoacid (ADK) inhibitors with HIV-1 integrase (IN) were studied via molecular docking method. The results indicate that the inhibitors bind to the pocket (formed by Asp64～Leu68, Thr115～Phe121, Gln148～Lys159 and Mg2＋ ion) of IN, and the inhibiting mechanism is similar to that of 5CITEP. Molecular dynamics simulation and MM/PBSA methods were used to calculate the binding free energy between ADK inhibitors and IN. The calculated binding free energy agrees well with experimental data, and the average absolute deviation is 3.6 kJ/mol. It was also found that the formation of the complex was mainly driven by the favorable van der Waals’(VDW) interactions in the system and the favorable non-polar item of the solvent effect. Correlation analysis shows that the binding free energy has obvious linear correlation with the hydrophobic interaction (R＝0.61), from which a good model predicting the binding free energy of ADK inhibitors with HIV-1 IN has been obtained through a multiple linear regression method. All the above simulation results provide us with some helpful instruction for the anti-HIV drug design based on the structures of inhibitors.