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ORIGINAL RESEARCH article

Front. Chem.
Sec. Medicinal and Pharmaceutical Chemistry
Volume 12 - 2024 | doi: 10.3389/fchem.2024.1449165

Computational Exploration of Acefylline Derivatives as MAO-B Inhibitors for Parkinson's disease: Insights from Molecular Docking, DFT, ADMET, and Molecular Dynamics Approaches

Provisionally accepted
Ali Irfan Ali Irfan 1*Yasir Ali Yasir Ali 2Yassir Boulaamane Yassir Boulaamane 3Sadia Javed Sadia Javed 4Huma Hameed Huma Hameed 5Ameer Fawad Zahoor Ameer Fawad Zahoor 6*Amal Maurady Amal Maurady 3Muhammed Tilahun Muhammed Muhammed Tilahun Muhammed 7Sajjad Ahmad Sajjad Ahmad 8Amal Al Mutairi Amal Al Mutairi 9Irum Shahzadi Irum Shahzadi 6Sami Al HUSSAIN Sami Al HUSSAIN 9Magdi E. Zaki Magdi E. Zaki 9*
  • 1 Government College University, Faisalabad, Faisalabad, Pakistan
  • 2 Institute of Chemistry, Slovak Academy of Sciences (SAS), Bratislava, Slovakia
  • 3 Faculty of Science and Technology of Tangier, Abdelmalek Essaadi University, Tangier, Morocco
  • 4 Department of Biochemistry, Government College University, Faisalabad, Faisalabad, Punjab, Pakistan
  • 5 Faculty of Pharmaceutical Sciences, University of Central Punjab, Lahore, Punjab, Pakistan
  • 6 Department of Chemistry, Government College University, Faisalabad, Faisalabad, Punjab, Pakistan
  • 7 Süleyman Demirel University, Isparta, Isparta, Türkiye
  • 8 Department of Health and Biological Sciences, Abasyn University, Peshawar, Khyber Pakhtunkhwa, Pakistan
  • 9 Department of Chemistry, College of Science, Imam Muhammad ibn Saud Islamic University, Riyadh, Saudi Arabia

The final, formatted version of the article will be published soon.

    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, forty-three acefylline derivatives were docked against 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 MAO-B14, MAO-B15, MAO-B16, MAO-B20, and MAO-B21 displayed binding affinities comparable to the both standards Istradefylline and Safinamide. These derivatives exhibiting hydrogen bonding interactions with key amino acids Phe167, Ile197/198, suggesting their strong potential as MAO-B inhibitors. Finally, molecular dynamics (MD) simulations were conducted to evaluate the stability of 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. 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 to evaluate their molecular interactions. These results were also validated by simulation based binding free energies via MM-GBSA method. However, it is necessary to conduct in vitro as well as in vivo experiments to confirm and validate these findings in future studies.

    Keywords: acefylline derivatives, Parkinson's disease, CADD approach, FBDD approach, MAO-B inhibitors, molecular docking, MD simulations, admet, drug-likeness, DFT studies

    Received: 14 Jun 2024; Accepted: 04 Sep 2024.

    Copyright: © 2024 Irfan, Ali, Boulaamane, Javed, Hameed, Zahoor, Maurady, Muhammed, Ahmad, Al Mutairi, Shahzadi, Al HUSSAIN and Zaki. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Ali Irfan, Government College University, Faisalabad, Faisalabad, Pakistan
    Ameer Fawad Zahoor, Department of Chemistry, Government College University, Faisalabad, Faisalabad, Punjab, Pakistan
    Magdi E. Zaki, Department of Chemistry, College of Science, Imam Muhammad ibn Saud Islamic University, Riyadh, Saudi Arabia

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