作为帕金森病 MAO-B 抑制剂的乙酰苯胺衍生物的计算探索:分子对接、DFT、ADMET 和分子动力学方法的启示。

IF 3.8 3区 化学 Q2 CHEMISTRY, MULTIDISCIPLINARY Frontiers in Chemistry Pub Date : 2024-10-08 eCollection Date: 2024-01-01 DOI:10.3389/fchem.2024.1449165
Ali Irfan, Ameer Fawad Zahoor, Yassir Boulaamane, Sadia Javed, Huma Hameed, Amal Maurady, Muhammed Tilahun Muhammed, Sajjad Ahmad, Aamal A Al-Mutairi, Irum Shahzadi, Sami A Al-Hussain, Magdi E A Zaki
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引用次数: 0

摘要

单胺氧化酶 B(MAO-B)在单胺(包括多巴胺和去甲肾上腺素等重要神经递质)的脱氨过程中发挥着关键作用。在发现 MAO-B 抑制剂有可能催化内源性和外源性神经毒性化合物的形成后,人们对 MAO-B 抑制剂的兴趣大增。计算筛选方法是寻找新型抑制剂的重要工具,可提高寻找工作的效率。本研究针对 MAO-B 酶对接了 43 种乙酰菲林衍生物,以考察它们的化疗潜力和结合亲和力,得出的 GOLD 适合度分数从 33.21 到 75.22 不等。其中,MAO-B14、MAO-B15、MAO-B16、MAO-B20 和 MAO-B21 这五种乙酰苯胺衍生物的结合亲和力与两种标准物质异替菲林和沙芬酰胺相当。这些衍生物表现出与关键氨基酸 Phe167 和 Ile197/198 的氢键相互作用,表明它们具有作为 MAO-B 抑制剂的强大潜力。最后,研究人员进行了分子动力学(MD)模拟,以评估所研究的乙酰苯胺衍生物随时间变化的稳定性。模拟结果表明,在所研究的乙酰胆碱衍生物和标准物质中,MAO-B21 是最稳定的候选物质。此外,还进行了密度泛函理论(DFT)研究以优化配体的几何结构,并进行了分子对接以预测配体在蛋白质结合腔内的取向并评估其分子相互作用。这些结果还通过分子力学能量结合广义玻恩和表面积溶解(MM-GBSA)方法的模拟结合自由能得到了验证。不过,有必要进行体外和体内实验,以便在今后的研究中证实和验证这些发现。
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Computational exploration of acefylline derivatives as MAO-B inhibitors for Parkinson's disease: insights from molecular docking, DFT, ADMET, and molecular dynamics approaches.

Monoamine oxidase B (MAO-B) plays a pivotal role in the deamination process of monoamines, encompassing crucial neurotransmitters like dopamine and norepinephrine. The heightened interest in MAO-B inhibitors emerged after the revelation that this enzyme could potentially catalyze the formation of neurotoxic compounds from endogenous and exogenous sources. Computational screening methodologies serve as valuable tools in the quest for novel inhibitors, enhancing the efficiency of this pursuit. In this study, 43 acefylline derivatives were docked against the MAO-B enzyme for their chemotherapeutic potential and binding affinities that yielded GOLD fitness scores ranging from 33.21 to 75.22. Among them, five acefylline derivatives, namely, MAO-B14, MAO-B15, MAO-B16, MAO-B20, and MAO-B21, displayed binding affinities comparable to the both standards istradefylline and safinamide. These derivatives exhibited hydrogen-bonding interactions with key amino acids Phe167 and Ile197/198, suggesting their strong potential as MAO-B inhibitors. Finally, molecular dynamics (MD) simulations were conducted to evaluate the stability of the examined acefylline derivatives over time. The simulations demonstrated that among the examined acefylline derivatives and standards, MAO-B21 stands out as the most stable candidate. Density functional theory (DFT) studies were also performed to optimize the geometries of the ligands, and molecular docking was conducted to predict the orientations of the ligands within the binding cavity of the protein and evaluate their molecular interactions. These results were also validated by simulation-based binding free energies via the molecular mechanics energies combined with generalized Born and surface area solvation (MM-GBSA) method. However, it is necessary to conduct in vitro and in vivo experiments to confirm and validate these findings in future studies.

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来源期刊
Frontiers in Chemistry
Frontiers in Chemistry Chemistry-General Chemistry
CiteScore
8.50
自引率
3.60%
发文量
1540
审稿时长
12 weeks
期刊介绍: Frontiers in Chemistry is a high visiblity and quality journal, publishing rigorously peer-reviewed research across the chemical sciences. Field Chief Editor Steve Suib at the University of Connecticut is supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to academics, industry leaders and the public worldwide. Chemistry is a branch of science that is linked to all other main fields of research. The omnipresence of Chemistry is apparent in our everyday lives from the electronic devices that we all use to communicate, to foods we eat, to our health and well-being, to the different forms of energy that we use. While there are many subtopics and specialties of Chemistry, the fundamental link in all these areas is how atoms, ions, and molecules come together and come apart in what some have come to call the “dance of life”. All specialty sections of Frontiers in Chemistry are open-access with the goal of publishing outstanding research publications, review articles, commentaries, and ideas about various aspects of Chemistry. The past forms of publication often have specific subdisciplines, most commonly of analytical, inorganic, organic and physical chemistries, but these days those lines and boxes are quite blurry and the silos of those disciplines appear to be eroding. Chemistry is important to both fundamental and applied areas of research and manufacturing, and indeed the outlines of academic versus industrial research are also often artificial. Collaborative research across all specialty areas of Chemistry is highly encouraged and supported as we move forward. These are exciting times and the field of Chemistry is an important and significant contributor to our collective knowledge.
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