In Vitro and in Silico Analysis of Phytochemicals From Fallopia dentatoalata as Dual Functional Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease.
In Vitro and in Silico Analysis of Phytochemicals From Fallopia dentatoalata as Dual Functional Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease.
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DOI：
10.3389/fphar.2022.905708
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发表时间：
2022
影响因子：
5.6
通讯作者：
Xue, Yongbo
中科院分区：
文献类型：
--
作者：
Wu, Yichuang;Su, Xiangdong;Lu, Jielang;Wu, Meifang;Yang, Seo Young;Mai, Yang;Deng, Wenbin;Xue, Yongbo
关键词：
目前研究发现，在阿尔茨海默病晚期，丁酰胆碱酯酶（BuChE）取代了乙酰胆碱酯酶（AChE）的生物学功能。番荔枝属植物富含多酚类化合物，化学结构多样，生物活性显著，是筛选抗AD天然产物的重要资源。本研究从齿瓣佛萝（Fallopia dentatoalata（Fr. Schm.）Holub，并测定其对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的抑制作用。苯丙素类蔗糖酯类化合物是该组中最有希望的成员，其中31-33显示出中度AChE抑制作用（IC 50值范围为30.6 ± 4.7至56.0 ± 2.4 µM），30-34显示出对BuChE的潜在抑制作用（IC 50值范围为2.7 ± 1.7至17.1 ± 3.4 µM）。使用他克林作为阳性对照（IC 50：AChE中为126.7 ± 1.1 nM，BuChE中为5.5 ± 1.7 nM）。动力学分析强调化合物31和32为AChE的非竞争性抑制剂，Ki值为1030.0和1034.4 μM，而30-34显示竞争性抑制BuChE，Ki值范围为101.8至1017.5 μM。分子结合研究表明，30-34与BuChE的催化位点结合，具有负结合能。体外和计算机模拟研究之间的强一致性突出了苯丙素类蔗糖酯30-34作为用于未来抗阿尔茨海默病的抗胆碱酯酶治疗剂的有希望的候选物。
Current studies have found that butyrylcholinesterase (BuChE) replaces the biological function of acetylcholinesterase (AChE) in the late stage of Alzheimer’s disease. Species in the genus of Fallopia, rich in polyphenols with diverse chemical structures and significant biological activities, are considered as an important resource for screening natural products to against AD. In this study, thirty-four compounds (1–34) were isolated from Fallopia dentatoalata (Fr. Schm.) Holub, and their inhibitory effects against AChE and BuChE were assessed. Compounds of the phenylpropanoid sucrose ester class emerged as the most promising members of the group, with 31–33 displaying moderate AChE inhibition (IC50 values ranging from 30.6 ± 4.7 to 56.0 ± 2.4 µM) and 30–34 showing potential inhibitory effects against BuChE (IC50 values ranging from 2.7 ± 1.7 to 17.1 ± 3.4 µM). Tacrine was used as a positive control (IC50: 126.7 ± 1.1 in AChE and 5.5 ± 1.7 nM in BuChE). Kinetic analysis highlighted compounds 31 and 32 as non-competitive inhibitors of AChE with Ki values of ∼30.0 and ∼34.4 µM, whilst 30–34 were revealed to competitively inhibit BuChE with Ki values ranging from ∼1.8 to ∼17.5 µM. Molecular binding studies demonstrated that 30–34 bound to the catalytic sites of BuChE with negative binding energies. The strong agreement between both in vitro and in silico studies highlights the phenylpropanoid sucrose esters 30–34 as promising candidates for use in future anti-cholinesterase therapeutics against Alzheimer’s disease.
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3.8
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