Bcl-2蛋白结合底物时的诱导契合及高效抑制剂的柔性对接研究

Bcl-2蛋白是目前抗肿瘤药物研究很具前景的新靶点. Bcl-2蛋白与底物作用的活性腔生理情况下是蛋白与蛋白作用接触面大而平坦, 与底物结合时发生明显的诱导契合. 通过分析和比较Bcl-2蛋白和其高同源的Bcl-x_L蛋白的自由状态及与底物复合时的9个相关三维结构模型, 明确了蛋白及活性腔的骨架结构特征, 活性腔内的重要位点和关键残基, 及它们结合底物时发生的诱导契合. 基于以上认识, 采用柔性对接的方法得到了高亲和力的小分子抑制剂与Bcl-2蛋白的合理结合模式, 为以后设计合成新型高效Bcl-2蛋白抑制剂打下了坚实基础.

Induced Fit When Binding Substrates of Bcl-2 Protein and Flexible Docking Study of a High Potent Inhibitor

Bcl-2 protein is a new target of anticancer drugs with bright prospect now. The active site of Bcl-2 protein is a protein-protein interface under physiological condition, and involves large and relatively flat surface areas and obvious induced fit when binding substrates. By analyzing and comparing nine correlative 3D structure models of Bcl-2 and homological Bcl-xL protein in free or complex state, the backbone structure features, key sites and induced fit of proteins and their active sites were identified. Based on above knowledge, a reasonable binding mode of a highly potent inhibitor to Bcl-2 has been developed using flexible docking techniques, which provides good basis for further design and synthesis of novel potent Bcl-2 protein inhibitors.