Acetylcholinesterase inhibitors are the mainstay of Alzheimer's disease treatments, despite having only short-term symptomatic benefits and severe side effects. Selective butyrylcholinesterase inhibitors (BuChEIs) may be more effective treatments in late-stage Alzheimer’s disease with fewer side effects. Virtual screening is a powerful tool for identifying potential inhibitors in large digital compound databases. This study used structure-based virtual screening combined with physicochemical filtering to screen the InterBioScreen and Maybridge databases for novel selective BuChEIs. The workflow rapidly identified 22 potential hits in silico, resulting in the discovery of a human BuChEI with low-micromolar potency in vitro (IC₅₀ 2.4 µM) and high selectivity for butyrylcholinesterase over acetylcholinesterase. The compound was a rapidly reversible BuChEI with mixed-model in vitro inhibition kinetics. The binding interactions were investigated using in silico molecular dynamics and by developing structure-activity relationships using nine analogues. The compound also displayed high permeability in an in vitro model of the blood-brain barrier.

乙酰胆碱酯酶抑制剂是阿尔茨海默氏病治疗的主要手段，尽管仅具有短期的症状益处和严重的副作用。选择性丁酰胆碱酯酶抑制剂（BuChEIs）在晚期阿尔茨海默氏病中可能是更有效的治疗方法，且副作用较少。虚拟筛选是在大型数字化合物数据库中识别潜在抑制剂的强大工具。这项研究使用基于结构的虚拟筛选结合物理化学过滤来筛选InterBioScreen和Maybridge数据库中的新型选择性BuChEI。该工作流程可快速识别出22种潜在的计算机突变，从而发现了具有低微摩尔效价的人BuChEI体外（IC ₅₀2.4 µM）对丁酰胆碱酯酶的选择性比乙酰胆碱酯酶高。该化合物是一种快速可逆的BuC​​hEI，具有混合模型的体外抑制动力学。使用计算机分子动力学和使用九种类似物建立结构-活性关系来研究结合相互作用。该化合物还在血脑屏障的体外模型中显示出高渗透性。