用分子模拟方法研究HIV-1整合酶与咖啡酰基类抑制剂的相互作用

Study on Interaction between HIV-1 Integrase and Its Dicaffeoyl Inhibitors through Molecular Modeling Approach

用分子对接和分子动力学(MD)模拟方法研究了一类咖啡酰基和没食子酰基类HIV-1整合酶抑制剂与整合酶之间的相互作用模式,结果表明该类抑制剂分子上的两个侧链基团(咖啡酰基或没食子酰基)与整合酶的DDE基序之间的相互作用对抑制整合酶活性起到关键作用.当侧链基团为没食子酰基时,可以提高该类抑制剂与整合酶的结合能力.采用线性相互作用能方法(LIE)计算了该类抑制剂与整合酶之间的结合自由能,预测值与实验值相吻合,均方根偏差RMSD为1.39kJ·mol-1,以上结果可为基于结构的HIV-1整合酶抑制剂设计提供有用的信息.

The binding mode of a series of dicaffeoyl or digalloyl pyrrolidine and furan derivatives inhibitors with HIV-1 integrase was proposed by using molecular docking and molecular dynamics （MD） simulation methods. The results indicate that the interactions between HIV-1 integrase conserved DDE motif and caffeoyl or galloyl group of inhibitors play a critical role in the inhibition of integrase activity, and the binding affinity between integrase and inhibitors was improved when the side chain groups were galloyls. The linear interaction energy （LIE） method was used to calculate the binding free energies of HIV-1 integrase and their inhJbitors, the predicted values are in good agreement with the experimental data, with a root-mean-square deviation （RMSD） of 1.39 kJ·mol^-1. The above results provide useful information for structure-based HIV-1 integrase inhibitor design.