In vitro and in silico investigation of FDA-approved drugs to be repurposed against Alzheimer's disease

IF 3.5 4区医学 Q2 CHEMISTRY, MEDICINAL Drug Development Research Pub Date : 2024-04-18 DOI:10.1002/ddr.22184

Didem Akkaya, Gökçe Seyhan, Suat Sari, Burak Barut

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Abstract

Alzheimer's disease (AD), one of the main causes of dementia, is a neurodegenerative disorder. Cholinesterase inhibitors are used in the treatment of AD, but prolonged use of these drugs can lead to serious side effects. Drug repurposing is an approach that aims to reveal the effectiveness of drugs in different diseases beyond their clinical uses. In this work, we investigated in vitro and in silico inhibitory effects of 11 different drugs on cholinesterases. The results showed that trimebutine, theophylline, and levamisole had the highest acetylcholinesterase inhibitory actions among the tested drugs, and these drugs inhibited by 68.70 ± 0.46, 53.25 ± 3.40, and 44.03 ± 1.20%, respectively at 1000 µM. In addition, these drugs are bound to acetylcholinesterase via competitive manner. Molecular modeling predicted good fitness in acetylcholinesterase active site for these drugs and possible central nervous system action for trimebutine. All of these results demonstrated that trimebutine was determined to be the drug with the highest potential for use in AD.

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对美国食品及药物管理局批准用于治疗阿尔茨海默病的药物进行体外和硅学研究

阿尔茨海默病（AD）是痴呆症的主要病因之一，是一种神经退行性疾病。胆碱酯酶抑制剂被用于治疗阿尔茨海默病，但长期使用这些药物会导致严重的副作用。药物再利用是一种旨在揭示药物在临床用途之外对不同疾病的疗效的方法。在这项工作中，我们研究了 11 种不同药物对胆碱酯酶的体外和体内抑制作用。结果表明，在受试药物中，曲美布汀、茶碱和左旋咪唑对乙酰胆碱酯酶的抑制作用最强，在 1000 µM 的浓度下，其抑制率分别为 68.70 ± 0.46、53.25 ± 3.40 和 44.03 ± 1.20%。此外，这些药物通过竞争方式与乙酰胆碱酯酶结合。分子建模预测，这些药物在乙酰胆碱酯酶活性位点的适配性良好，三丁酸可能具有中枢神经系统作用。所有这些结果表明，曲美布汀被确定为最有可能用于治疗注意力缺失症的药物。

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来源期刊

Drug Development Research 医学-药学

CiteScore

6.40

自引率

2.60%

发文量

104

审稿时长

6-12 weeks

期刊介绍： Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.