Computational exploration of acefylline derivatives as MAO-B inhibitors for Parkinson's disease: insights from molecular docking, DFT, ADMET, and molecular dynamics approaches.

Autor: Irfan A; Department of Chemistry, Government College University Faisalabad, Faisalabad, Pakistan., Zahoor AF; Department of Chemistry, Government College University Faisalabad, Faisalabad, Pakistan., Boulaamane Y; Laboratory of Innovative Technologies, National School of Applied Sciences of Tangier, Abdelmalek Essaadi University, Tetouan, Morocco., Javed S; Department of Biochemistry, Government College University Faisalabad, Faisalabad, Pakistan., Hameed H; Faculty of Pharmaceutical Sciences, University of Central Punjab, Lahore, Pakistan., Maurady A; Laboratory of Innovative Technologies, National School of Applied Sciences of Tangier, Abdelmalek Essaadi University, Tetouan, Morocco., Muhammed MT; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Suleyman Demirel University, Isparta, Türkiye., Ahmad S; Department of Health and Biological Sciences, Abasyn University Peshawar, Peshawar, Pakistan.; Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon.; Department of Natural Sciences, Lebanese American University, Beirut, Lebanon., Al-Mutairi AA; Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia., Shahzadi I; Department of Chemistry, Government College University Faisalabad, Faisalabad, Pakistan., Al-Hussain SA; Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia., Zaki MEA; Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia.
Jazyk: angličtina
Zdroj: Frontiers in chemistry [Front Chem] 2024 Oct 08; Vol. 12, pp. 1449165. Date of Electronic Publication: 2024 Oct 08 (Print Publication: 2024).
DOI: 10.3389/fchem.2024.1449165
Abstrakt: 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.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Irfan, Zahoor, Boulaamane, Javed, Hameed, Maurady, Muhammed, Ahmad, Al-Mutairi, Shahzadi, Al-Hussain and Zaki.)
Databáze: MEDLINE
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