HIV-1跨膜蛋白gp41与N-取代吡咯衍生物的结合模式研究

采用分子对接，分子动力学(MD)模拟和分子力学/泊松-波尔兹曼溶剂可有面积方法与分子力学/广义伯恩溶剂可及面积方法(MM-PBSA/MM-GBSA)，预测两种N-取代吡咯衍生物与HIV-1 跨膜蛋白gp41疏水口袋的结合模式与作用机理．分子对接采用多种受体构象，并从结果中选取几种可能的结合模式进行MD 模拟，然后通过MM-PBSA计算结合能的方法识别最优的结合模式. MM-PBSA计算结果表明，范德华相互作用是结合的主要驱动力，而极性相互作用决定了配体在结合过程中的取向．进一步的结合能分解显示，配体的羧基与gp41残基Arg579的静电相互作用对结合有重要贡献．上述工作为进一步优化N-取代吡咯衍生物类的HIV-1融合抑制剂建立了良好的理论基础．

Computational Study of Binding Mode for N-substituted Pyrrole Derivatives to HIV-1 gp41

Molecular docking, molecular dynamics (MD) simulation and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA)/molecular mechanics Generalized Born surface area (MM-GBSA) analysis are applied to predict the binding mode of two N-substituted pyrrole derivate inhibitors to the hydrophobic pocket in HIV-1 envelope protein gp41. Taking into account the flexibility of the receptor, multiple receptor conformations are used in docking with the ligands, which results in several possible binding modes. MD simulations and MM-PBSA binding energy calculations are performed on all the binding modes to identify the most favorable binding estimate. The MM-PBSA results indicate that the binding is mainly driven by non-polar interactions, while polar interactions determine the orientation of the ligands binding into the target site. Further analysis reveals the key residues and ligand-receptor interactions which contribute significantly to the binding affinity. This study provides useful information for rational design and optimization of N-substituted pyrrole derivatives as HIV-1 fusion inhibitors.