作用于秋水仙碱位点的微管蛋白抑制剂的结合模式 研究与结构模型的构建

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.

Study on the Binding Modes of the Colchicine-site Inhibitors and Construction of Their Structural Model

By docking simulation, the binding modes of the colchicine-site inhibitors with β-tubulin and their structural model were constructed. The results showed that the inhibitors mainly depended on the hydrophobic interactions with the hydrophobic pockets I and II, and on the hydrogen-bonds with α-Thr178, α-Val181 and β-Cys241. According to their binding conformations, the structures of the inhibitors were divided into three parts, namely A, B and the bridge between them. The structural model of the inhibitor (the hydrophobic centers H1 and H2, the hydrophobic group H3, the hydrogen-bond acceptors A1 and A2 and the polar atom P) was built. The main factors of H1 and H2 are the volume size, and the planarity, while the bridge part should be in rigid form to maintain parts A and B to be in the same side of the bridge (in cis-conformation). A potential hydrogen-bond acceptor A3 was proposed between A2 and the loop area.