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采用对接的方法建立了秋水仙碱位点抑制剂与微管蛋白的结合模式,并构建了其结构模型.结果表明:抑制剂主要借助于与口袋I和II的疏水作用,以及同α-Thr178,α-Val181和β-Cys241之间的氢键来实现与微管蛋白的结合.根据抑制剂的结合构象,将抑制剂的结构分为A,B以及AB间的桥连三个部分,从而建立了由A部分中的疏水中心H1、氢键受体A1,B部分中的疏水中心H2、疏水基团H3和极性原子P以及桥连结构中的氢键受体A2组成的结构模型.并指出H1与H2对活性的影响因素分别为疏水基团的体积和平面特征,而桥连部分则应以刚性的形式保证AB处于桥连的同侧(即顺式构象).还提出在A2与loop区之间存在一个的潜在氢键受体A3.研究结果为设计新型小分子微管蛋白抑制剂提供指导.
The binding mode of colchicine site inhibitor and tubulin was established by docking method, and its structural model was constructed.The results showed that the inhibitor was mainly caused by the hydrophobic interaction with pocket I and II, and the same with α-Thr178 , α-Val181 and β-Cys241.Based on the binding conformation of inhibitor, the structure of inhibitor is divided into three parts of bridge between A, B and AB A structural model consisting of hydrophobic center H1, hydrogen bond acceptor A1 in part A, hydrophobic center H2 in hydrophobic part H3, hydrophobic group H3 and polar atom P, and hydrogen bond acceptor A2 in the bridged structure was established. It is pointed out that the influencing factors of H1 and H2 on the activity are respectively the volume and planar features of the hydrophobic groups, while the bridging part should ensure that AB is in the same side of the bridging (ie cis conformation) in a rigid form. And the loop region between the existence of a potential hydrogen bond receptor A3.The results provide guidance for the design of novel small molecule tubulin inhibitors.