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Sinefungin analogs targeting VP39 methyltransferase as potential anti-monkeypox therapeutics: a multi-step computational approach

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Abstract

The increasing spread of the Monkeypox virus (MPXV) presents a significant public health challenge, emphasising the urgent requirement for effective treatments. Our study focuses on the VP39 Methyltransferase enzyme of MPXV as a critical target for therapy. By utilising virtual screening, we investigated natural compounds with structural similarities to sinefungin, a broad-acting MTase inhibitor. From an initial set of 177 compounds, we identified three promising compounds—CNP0346326, CNP0343532, and CNP008361, whose binding scores were notably close to that of sinefungin. These candidates bonded strongly to the VP39 enzyme, hinting at a notable potential to impede the virus. Our rigorous computational assays, including re-docking, extended molecular dynamics simulations, and energetics analyses, validate the robustness of these interactions. The data paint a promising picture of these natural compounds as front-runners in the ongoing race to develop MPXV therapeutics and set the stage for subsequent empirical trials to refine these discoveries into actionable medical interventions.

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Funding

This research has been funded by Scientific Research Deanship at University of Ha’il - Saudi Arabia through project number RG-23 204.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, College of Pharmacy, University of Hail, 81442, Hail, Saudi Arabia

    Amr S. Abouzied, Bader Huwaimel, Saad Alqarni & Kareem M. Younes

  2. Medical and Diagnostic Research Center, University of Hail, 55473, Hail, Saudi Arabia

    Amr S. Abouzied & Bader Huwaimel

  3. Department of Analytical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt

    Kareem M. Younes

  4. College of Pharmacy, University of Hail, 81442, Hail, Saudi Arabia

    Rakan E. Alshammari, Abdulkarim H. Alshammari & Wadaah F. Algharbi

  5. Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, El-Sadat, Egypt

    Akram M. Elkashlan

Authors
  1. Amr S. Abouzied
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  5. Rakan E. Alshammari
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Contributions

ASA, BH, SA, KMY, REA, AHA, WFA, and AME contributed towards conceptualisation. ASA contributed towards supervision. ASA, BH, SA, KMY, REA, AHA, WFA, and AME contributed towards the methodology and data analysis. ASA and BH contributed towards writing—original draft preparation. ASA, BH, SA, KMY, REA, AHA, WFA, and AME contributed towards Writing—review & editing. All authors reviewed the manuscript.

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Correspondence to Amr S. Abouzied.

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Abouzied, A.S., Huwaimel, B., Alqarni, S. et al. Sinefungin analogs targeting VP39 methyltransferase as potential anti-monkeypox therapeutics: a multi-step computational approach. Mol Divers (2024). https://doi.org/10.1007/s11030-024-10875-z

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