Wang Erxu, Zhang Huiran, Li Xiangchuan, Geng Lili, Wang Zhen, Chu Airong, Lu Bin, Duan Li
Hebei Key Laboratory of Organic Functional Molecules, College of Chemistry and Materials Science, Hebei Normal University, Shijiazhuang, Hebei 050024, China.
Hebei Key Laboratory of Organic Functional Molecules, College of Chemistry and Materials Science, Hebei Normal University, Shijiazhuang, Hebei 050024, China.
J Pharm Biomed Anal. 2025 Nov 15;265:117067. doi: 10.1016/j.jpba.2025.117067. Epub 2025 Jul 15.
Alzheimer's disease (AD) is a common neurodegenerative disease, and is characterized by impaired acetylcholine-mediated neurotransmission. Acetylcholinesterase (AChE) inhibition is a well-established therapeutic strategy for AD. Medicinal plants exhibit multi-target effects, low toxicity, and cost-effectiveness. Therefore, screening AChE inhibitors from botanical sources holds considerable pharmacological potential. In this study, a metal-organic framework was used as a novel support for immobilizing AChE, resulting in the creation of AChE@MIL-88B-NH, which served as a tool for screening potential AChE inhibitors. The immobilized enzyme exhibited excellent reusability, stability against pH fluctuations and thermal stress, and resistance to organic solvents. The constructed AChE@MIL-88B-NH-based ligand fishing strategy coupled with mass spectrometry was applied to screen for AChE inhibitors in Nelumbinis plumula extracts. Seven compounds were identified as potent AChE inhibitors. Enzyme kinetic assays revealed that these ligands exhibit a mixed inhibition mechanism against AChE. Molecular docking demonstrated that the seven compounds effectively bound to the AChE active site, with binding affinities ranging from -9.7 to -8.5 kcal/mol. The established AChE@MIL-88B-NH-based ligand fishing strategy provides a simple and efficient approach for screening potential AChE inhibitors from complex botanical matrices, offering a promising avenue for discovering novel therapeutic agents for AD.
阿尔茨海默病（AD）是一种常见的神经退行性疾病，其特征是乙酰胆碱介导的神经传递受损。抑制乙酰胆碱酯酶（AChE）是一种成熟的AD治疗策略。药用植物具有多靶点作用、低毒性和成本效益。因此，从植物来源筛选AChE抑制剂具有相当大的药理学潜力。在本研究中，一种金属有机框架被用作固定AChE的新型载体，从而制备出AChE@MIL-88B-NH，它作为筛选潜在AChE抑制剂的工具。固定化酶表现出优异的可重复使用性、对pH波动和热应激的稳定性以及对有机溶剂的耐受性。构建的基于AChE@MIL-88B-NH的配体垂钓策略与质谱联用，用于筛选莲子提取物中的AChE抑制剂。七种化合物被鉴定为有效的AChE抑制剂。酶动力学分析表明，这些配体对AChE表现出混合抑制机制。分子对接表明，这七种化合物有效地结合到AChE活性位点，结合亲和力范围为-9.7至-8.5 kcal/mol。所建立的基于AChE@MIL-88B-NH的配体垂钓策略为从复杂植物基质中筛选潜在AChE抑制剂提供了一种简单有效的方法，为发现AD的新型治疗药物提供了一条有前景的途径。
