甲基苯并唑衍生物与HIV-1逆转录酶相互作用的分子模拟研究

对HIV-1逆转录酶(RT)与二氟甲基苯并唑甲基嘧啶硫醚(DFMMT)及甲基苯并唑甲基嘧啶硫醚(MMT)两个甲基苯并唑衍生物的复合物进行了分子动力学模拟,从分子整体、结合模式优化和水分子作用3个角度详细分析了甲基苯并唑衍生物与HIV-1 RT相互识别的机制.结果表明,DFMMT和MMT在RT中的结合位点几乎一致；但DFMMT与RT的π-π堆积作用更强.另外,RT的DFMMT结合口袋中有3个稳定的水分子存在,而MMT结合则没有水分子参与.3个水分子的协同使得DFMMT与RT的相互作用强于MMT,这可能是双氟促进抑制活性的作用机制之一.

Molecular Modeling Study on the Interactions between Methylbenzoxazole Derivatives and HIV-1 Reverse Transcriptase

Two molecular dynamics simulations were performed for HIV-1 RT complexed with two methylbenzoxazole derevatives,difluoro-methylbenzoxazole methylpyrimidine thioether(DFMMT) and methylbenzoxazole methylpyrimidine thioether(MMT).The inter-recognition between HIV-1 RT and two methylbenzoxazole derevatives were detailedly analyzed from the aspects of overall structure,binding modes minimization and the key role of water molecules.The results showed that the binding site between DFMMT and RT was almost the same with that of MMT,while the π-π stacking action of DFMMT with RT was stronger than of MMT.In addition,it was found that there were three stably water molecules existing in the binding pocket of RT for DFMMT,while no water participated in the association between RT and high hydrophobic MMT.The cooperation of the three water molecules made the interaction between DFMMT and RT stronger than that of MMT,which may be one of the action mechanisms of difluorin favoring the inhibitory activity.