[关键词]
[摘要]
目的阐明连翘苷D(FTD)与凝血因子Xa(FXa)活性位点的动态相互作用过程,为设计新药提供参考依据。方法利用FXa蛋白与其原始配体(RPR)的合理复合物结构作参照物,通过对接获得了FTD与FXa的复合结构。采用分子动力学方法模拟了两个复合物在水溶液中500 ps运动轨迹,考察配体与受体在动态相互作用过程中的变化过程。结果RPR依靠氢键作用与受体S1区域和中间部保持稳定的匹配状态,以非极性的芳香基与S4区域(Tyr99、Phe174、Trp215)形成了很好的空间匹配。FTD与受体相互作用方式不同,与受体的S1区域作用较弱,相对而言与S4区域及中间部的作用较强,导致在相互作用的过程中被受体排斥出来。结论通过配体与受体动态相互作用模拟研究表明,作为FXa的抑制剂与受体S1区结合的部分结构应该相对刚性,能与受体形成较强的氢键,在S4区需要一定的疏水性和芳香性,在中间部分需要一定量的氢键来帮助固定配体。
[Key word]
[Abstract]
Objective To illuminate the dynamic interactive mode between coagulation factor Xa(FXa) active site and forsythoside D(FTD),in order to supply some advices for the design of new drugs.Methods To make FXa protein receptor and its initial ligand(RPR) as a reasonable compound and obtain a compound structure of FTD and FXa by using molecular docking.In order to investigate the interaction of the ligand and receptor during the dynamic state,500 ps molecular dynamics simulation was chosen to estimate their binding mode.Results RPR remained stable matching state with S1 domain and middle part of the receptor depending on hydrogen bond,formed fine spacial matching with S4(Tyr99,Phe174,and Trp215) relying on nonpolarity aromatic groups.The interaction style of FTD and receptor is different from RPR,it had weak role with S1 domain but had relatively strong action with S4 and middle part,as a result the ligand was repelled from the receptor.Conclusion Through the dynamic simulation of the interaction of ligand and receptor,it suggested that part of the structure of FXa inhibitor which can combine with S1 domain of receptor should be relatively rigid and it can form strong hydrogen bond with receptor.In the S4 domain of the receptor,it needs some hydrophobic,aromatic groups,and some hydrogen bond in the middle part to help fix the ligand.
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[基金项目]
科技部支撑项目(2007BAI41B00);天津市支撑项目(07ZCKFSH00300)