Rational Design of New Class of BH3-Mimetics As Inhibitors of the Bcl-x_L Protein

The Bcl-2 family of proteins plays an important role in the intrinsic pathway of cell apoptosis. Overexpression of pro-survival members of this family of proteins is often associated with the development of many types of cancer and confers resistance against conventional therapeutic treatments. Accordingly, antagonism of its protective function has emerged as an encouraging anticancer strategy. In the present work, we use a pharmacophore for describing interaction between the BH3 domain of different pro-apoptotic members and the pro-survival protein Bcl-xL in order to identify new lead compounds. In the strategy followed in the present work, the pharmacophore was derived from molecular dynamics studies of different Bcl-xL/BH3 complexes. This pharmacophore was later used as query for 3D database screening. Hits obtained from the search were computationally assessed, and a subset proposed for in vitro testing. Two of the 15 compounds assayed were found able to disrupt the Bcl-xL/Bak(BH3) complex with IC50 values in the lower micromolar range. Finally, docking studies were performed to explore the binding mode of these compounds to Bcl-xL for further modifications.Bcl-2家族蛋白在细胞凋亡的内源性通路中发挥着关键作用。该家族中促存活蛋白成员的过度表达，常与多种癌症的发生发展相关，并会使肿瘤细胞对常规治疗手段产生耐药性。因此，靶向拮抗其保护功能已成为颇具前景的抗癌策略。在本研究中，我们采用药效团（pharmacophore）来描述不同促凋亡蛋白成员的BH3结构域与促存活蛋白Bcl-xL之间的相互作用，以期发现新型先导化合物。本研究采用的药效团，源自对不同Bcl-xL/BH3复合物开展的分子动力学研究。随后，该药效团被用作查询模板进行三维数据库筛选。对筛选得到的命中化合物进行了计算评估，并从中选取了一部分用于体外实验。在检测的15种化合物中，有2种能够破坏Bcl-xL/Bak(BH3)复合物，其IC50值处于低微摩尔级别。最后，我们通过对接研究探索了这些化合物与Bcl-xL的结合模式，以便开展后续的结构修饰。