The cholinesterases are essential targets implicated in the pathogenesis of Alzheimer’s disease (AD). In the present study, virtual screening and molecular docking are performed to identify the potential hits. Docking-post processing (DPP) and pose filtration protocols against AChE and BChE resulted in three hits (AW00308, HTS04089, and JFD03947). Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) and molecular dynamics simulation analysis affirmed the stability and binding pattern of the docked complex JFD03947, which was further synthesized and evaluated for in vitro cholinesterase inhibition (AChE, IC₅₀ = 0.062 µM; BChE, IC₅₀ = 1.482 µM) activity. The enzyme kinetics study of the JFD03947 against hAChE and hBChE suggested a mixed type of inhibition. The results of thioflavin T-assay also elicited anti-Aβ aggregation activity by JFD03947. Further, biological evaluation of identified compound JFD03947 also showed neuroprotective ability against the SH-SY5Y neuroblastoma cell lines.

胆碱酯酶是与阿尔茨海默病 (AD) 发病机制有关的重要靶标。在本研究中，进行虚拟筛选和分子对接以识别潜在的命中。针对 AChE 和 BChE 的对接后处理 (DPP) 和姿势过滤协议导致三个命中（AW00308、HTS04089 和 JFD03947）。分子力学-广义出生表面积 (MM-GBSA) 和分子动力学模拟分析证实了对接复合物 JFD03947 的稳定性和结合模式，进一步合成并评估了体外胆碱酯酶抑制作用（AChE，IC ₅₀  = 0.062 µM；BChE , IC ₅₀ = 1.482 µM) 活动。JFD03947 对 hAChE 和 hBChE 的酶动力学研究表明存在混合类型的抑制作用。硫代黄素 T 测定的结果也引发了 JFD03947 的抗 Aβ 聚集活性。此外，鉴定的化合物 JFD03947 的生物学评估也显示出对 SH-SY5Y 神经母细胞瘤细胞系的神经保护能力。