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10 μM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 discovery (FBDD) has been widely applied in the research of aspartyl protease inhibitors.In the present study,we reported our work on 2-aminobenzimidazole as the original fragment,which was predicted to bind with the catalytic aspartyl dyad (Asp228 and Asp32) of β-site amyloid precursor protein cleaving enzyme 1 (BACE1).A series of novel 2-aminobenzimidazole derivatives were designed and synthesized.The results from FRET assay revealed that three out of the 12 designed 2-aminobenzimidazoles could inhibit more than 50％ of the enzymatic potency of BACE1 at 10 μM.Docking study showed that 2-aminobenzimidazole could form multiple hydrogen bonds and occupy S1/S2’pockets well.