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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。
Objective To elucidate the dynamic interaction between Forsythin D (FTD) and coagulation factor Xa (FXa) active sites, and to provide a reference for the design of new drugs. Methods The rational complex structure of FXa protein and its original ligand (RPR) was used as a reference, and the complex structure of FTD and FXa was obtained by docking. The 500 ps trajectory of two complexes in aqueous solution was simulated by molecular dynamics method, and the change process of ligand and receptor during dynamic interaction was investigated. Results RPR relied on the hydrogen bond to maintain a stable match with the S1 region and the middle region of the receptor. The non-polar aromatic group formed a good spatial match with the S4 region (Tyr99, Phe174 and Trp215). The mode of interaction of FTD with receptor is different, and it has weaker interaction with receptor S1, and relatively strong interaction with S4 and middle, which leads to rejection by receptor in the process of interaction. Conclusions The dynamic interaction between ligand and receptor shows that the partial structure of FXa as an inhibitor binds to the S1 region of the receptor and should be relatively rigid and capable of forming strong hydrogen bonds with the receptor. Sexual and aromatic, in the middle part of the need for a certain amount of hydrogen bonds to help fix the ligand.