论文部分内容阅读
基于片段的药物设计(FBDD)在天冬氨酰蛋白酶抑制剂的研究中有广泛的应用。本文针对可与BACE1催化活性中心Asp228和Asp32形成氢键作用的2-氨基苯并咪唑这一分子片段,通过对其结合模式的分析以及相关文献晶体结构的指导,进行了一系列的结构修饰。在设计合成的12个化合物中有三个化合物在10μM水平的体外酶水平抑制实验中显示了大于50%的抑制活性。分子对接显示这一系列化合物可以形成多重的氢键作用并占据BACE1活性中心的S1和S2’口袋,未来可能会成为研究潜在新型BACE1抑制剂的良好开端。
Fragment-based drug design (FBDD) is widely used in the study of aspartyl protease inhibitors. In this paper, a series of structural modifications of 2-aminobenzimidazole, which can form hydrogen bonds with Asp228 and Asp32, of BACE1 catalytic center, were carried out through the analysis of their binding modes and the guidance of the crystal structure of related literature. Three of the 12 compounds that were designed and synthesized showed greater than 50% inhibitory activity in an in vitro enzyme level inhibition assay at the 10 μM level. Molecular docking shows that this series of compounds can form multiple hydrogen bonds and occupy the S1 and S2 ’pocket of the BACE1 active site and may well open the door to potential new BACE1 inhibitors.