通过虚拟筛选过滤天然衍生物作为 MAO 抑制剂:治疗神经退行性疾病的潜在药物。

Neelam Malik, Supriya Agnihotri, Priyanka Dhiman
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引用次数: 0

摘要

目的本研究旨在探索虚拟库,以筛选单胺氧化酶(MAO)同工酶。本研究的主要目的是筛选和验证天然配体对 MAO 的抑制作用,同时将其不良反应降至最低,并从分子方面对最具活性的先导分子进行进一步的结构修饰。背景MAO 在控制中枢神经系统活动方面的重要性已得到广泛研究。我们在这项工作中的目标是找出对 MAO 酶具有更强亲和力的潜在天然先导分子,以便生产出更有效的天然候选神经药物。对于 MAO-B,鼠李素、槲皮素、胡椒碱、丁香酚和伞形酮的对接得分最高,分别为 -10.57、-9.938、-9.445 和 7.821。对于 MAO-A、伞形酮、姜黄素、咖啡酸和槲皮素,相应的对接得分分别为-8.001、-7.941、-7.357 和 -6.658。此外,还利用体外 MAO 抑制实验来评估对接得分最高的化合物。结果发现,最有效的人类单胺氧化酶(hMAO-A)抑制剂是化合物伞形酮(umbelliferone),其 IC50 为 10.98±0.006 M,选择性指数(SI)为 0.607。结论发现这些天然潜在配体对 MAO-A 和 MAO-B 的抑制作用优于标准化合物,可用作开发新型候选治疗药物的先导化学品。硅学筛选结果与体外 hMAO 抑制功效表现出很强的相关性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Filtration of Natural Derivatives as MAO Inhibitors by Virtual Screening: A Potential Lead for Neurodegenerative Disorders.
AIM The purpose of the current study was to explore the virtual library for the screening against Monoamine oxidase (MAO) isoforms. An in-house library of natural based ligands was docked within the active sites of MAO isoforms and their in vitro study was also conducted. OBJECTIVE The prime objective of the current study was to screen and validate the natural-based derivatives for MAO inhibitory action with the least adverse effects and get molecular aspects about further structural modifications on the most active leads. BACKGROUND The importance of MAOs in controlling the activity of the central nervous system has been extensively studied. Our goal in this work is to identify a prospective natural lead molecule that has a stronger affinity for the MAO enzyme in order to produce a more effective natural candidate for a neurological agent. RESULTS In order to get insight into how different categories of natural compounds interact with the targeted protein, we virtually screened the numerous natural compound categories in the current study. Rhamnetin, quercetin, piperine, eugenol, and umbelliferone showed the highest dock scores in the case of MAO-B, with scores of -10.57, -9.938, -9.445, and 7.821, respectively. For MAO-A, umbelliferone, curcumin, caffeic acid, and quercetin, the corresponding dock scores were -8.001, -7.941, -7.357, and -6.658. Additionally, an in vitro MAO inhibitory experiment was utilized to assess the top-ranked compounds with the best docking scores. The most potent Human Monoamine oxidase (hMAO-A) inhibitor, with an IC50 of 10.98±0.006 M and a selectivity index (SI) of 0.607, was discovered to be the compound umbelliferone. Rhamnetin, the lead chemical, has demonstrated hMAO-B activity with a value of 10.32±0.044 M (SI value of 3.096). CONCLUSION These natural potential ligands have been found remarkable to the standard compounds against MAO-A and MAO-B, and they could be used as a lead chemical in the development of novel therapeutic candidates. The in silico screening results and in vitro hMAO inhibitory efficacy exhibited strong correlations.
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