Background: Alzheimer’s disease is a neurological condition causing cognitive inability and dementia. The pathological lesions and neuronal damage in the brain are caused by self-aggregated fragments of mutated Amyloidal precursor protein (APP).

Objective: The controlled APP processing by inhibition of secretase is the strategy to reduce Aβ load to treat Alzheimer’s disease.

Methods: A QSAR study was performed on 55 Pyrrolidine based ligands as BACE-1 inhibitors with an activity magnitude greater than 4 of compounds.

Results: In the advent of designing new BACE-1 inhibitors, the pharmacophore model with correlation (r = 0.90) and root mean square deviation (RMSD) of 0.87 was developed and validated. Further, the hits retrieved by the in-silico approach were evaluated by docking interactions.

Conclusion: Two structurally diverse compounds exhibited Asp32 and Thr232 binding with the BACE-1 receptor. The aryl-substituted carbamate compound exhibited the highest fit value and docking score. The biological activity evaluation by in-vitro assay was found to be >0.1μM.

背景：阿尔茨海默病是一种导致认知障碍和痴呆的神经系统疾病。大脑中的病理损伤和神经元损伤是由突变的淀粉样前体蛋白 (APP) 的自聚集片段引起的。

目的：通过抑制分泌酶控制APP加工是降低Aβ负荷治疗阿尔茨海默病的策略。

方法：对 55 种基于吡咯烷的配体作为 BACE-1 抑制剂进行 QSAR 研究，其活性量级大于 4 种化合物。

结果：随着设计新 BACE-1 抑制剂的出现，开发并验证了相关性 (r = 0.90) 和均方根偏差 (RMSD) 为 0.87 的药效团模型。此外，通过对接交互评估由计算机内方法检索到的命中。

结论：两种结构不同的化合物表现出 Asp32 和 Thr232 与 BACE-1 受体的结合。芳基取代的氨基甲酸酯化合物表现出最高的拟合值和对接分数。发现体外测定的生物活性评价>0.1μM。