Laboratoire Des Sciences Fondamentales, Université Amar Telidji, Laghouat 03000, Algérie.
Département De Biologie, Université Amar Telidji, Laghouat 03000, Algérie.
Curr Comput Aided Drug Des. 2023;19(3):176-191. doi: 10.2174/1573409919666221104093218.
The present study aimed to identify new selective inhibitors for acetylcholinesterase, butyrylcholinesterase, monoacylglycerol lipase, beta-secretase, and Asparagine endopeptidase, the targets enzymes in Alzheimer's disease.
The inhibitory effect of P. atlantica Desf. methanol extracts against AChE were determined using Ellman's method. The molecular docking study is achieved using Autodock Vina. The structures of the molecules 3-methoxycarpachromene, masticadienonic acid, 7-ethoxycoumarin, 3',5,7- trihydroxy-4'-methoxyflavanone and 5,6,7,4'-tetrahydroxyflavonol-3-O-rutinoside and the five enzymes were obtained from the PubChem database and Protein databank. ADMET parameters were checked to confirm their pharmacokinetics using swiss-ADME and ADMET-SAR servers.
P. atlantica Desf. methanol extracts showed a notable inhibitory effect against AChE (IC = 0.26 ± 0.004 mg/ml). The molecular docking results of 3-methoxycarpachromene, masticadienonic acid, 7-ethoxycoumarin, 3',5,7-trihydroxy-4'-methoxyflavanone and 5,6,7,4'-tetrahydroxyflavonol-3-Orutinoside with the five enzymes show significant affinities of these molecules towards Alzheimer disease targets, where they could form several interactions, such as hydrogen bonds and hydrophobic interactions with the studied enzymes. The shortest hydrogen bond is 1.7 A° between masticadienonic acid and Arg128 of the active site of BACE, while the lowest free energy is -11.2 of the complex 5,6,7,4'-tetrahydroxyflavonol-3-O-rutinoside -HuBchE. To the best of our knowledge, these molecules' potential anti-Alzheimer disease effect is studied in this paper for the first time.
The docking studies of this work show that 3-methoxycarpachromene and masticadienonic acid, 7-ethoxycoumarin, 3',5,7-Trihydroxy-4'-methoxyflavanone and 5,6,7,4'-tetrahydroxyflavonol- 3-O-rutinoside have good affinities towards the enzymes involved in Alzheimer pathology, which confirm the ability of these molecules to inhibit the studied enzymes namely: HuAChE, HuBChE, BACE, MAGL, and AEP. These molecules might become drug candidates to prevent Alzheimer's disease.
本研究旨在寻找新的乙酰胆碱酯酶、丁酰胆碱酯酶、单酰甘油脂肪酶、β-分泌酶和天冬酰胺内肽酶选择性抑制剂，这些都是阿尔茨海默病的靶点酶。
采用 Ellman 法测定扁枝槲寄生甲醇提取物对乙酰胆碱酯酶的抑制作用。采用 Autodock Vina 进行分子对接研究。从 PubChem 数据库和 Protein databank 获得 3-甲氧基卡帕烯、乳香酸、7-乙氧基香豆素、3'，5，7-三羟基-4'-甲氧基黄烷酮和 5，6，7，4'-四羟基黄酮醇-3-O-芦丁糖苷以及 5 种酶的分子结构。使用 swiss-ADME 和 ADMET-SAR 服务器检查 ADMET 参数，以确认其药代动力学性质。
扁枝槲寄生甲醇提取物对乙酰胆碱酯酶（IC = 0.26 ± 0.004 mg/ml）具有显著的抑制作用。3-甲氧基卡帕烯、乳香酸、7-乙氧基香豆素、3'，5，7-三羟基-4'-甲氧基黄烷酮和 5，6，7，4'-四羟基黄酮醇-3-O-芦丁糖苷与 5 种酶的分子对接结果表明，这些分子对阿尔茨海默病靶点具有显著的亲和力，它们可以与研究酶形成多种相互作用，如氢键和疏水相互作用。乳香酸与 BACE 活性部位的 Arg128 之间的最短氢键为 1.7 A°，而 5，6，7，4'-四羟基黄酮醇-3-O-芦丁糖苷-HuBchE 的最低自由能为-11.2。据我们所知，这些分子的潜在抗阿尔茨海默病作用在本文中是首次研究。
本工作的对接研究表明，3-甲氧基卡帕烯和乳香酸、7-乙氧基香豆素、3'，5，7-三羟基-4'-甲氧基黄烷酮和 5，6，7，4'-四羟基黄酮醇-3-O-芦丁糖苷对阿尔茨海默病相关酶具有良好的亲和力，这证实了这些分子抑制研究酶的能力，即：HuAChE、HuBChE、BACE、MAGL 和 AEP。这些分子可能成为预防阿尔茨海默病的候选药物。
