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Background <p>The resurgence of MonkeyPox Virus (MPXV) and its potential for human-to-human transmission demands the urgent need for novel antiviral agents. Among MPXV’s proteins, the A42R profilin-like protein, implicated in cytoskeletal manipulation and viral pathogenesis, presents an attractive therapeutic target. This study employs an integrative in silico approach to identify natural product-based inhibitors of A42R, utilizing molecular docking, Molecular Dynamics (MD) simulations, and MM/GBSA binding free energy analysis. </p> Methods <p>A curated library of natural compounds and secondary metabolites from DrugBank and KNApSAcK databases was screened against the A42R structure (PDB ID: 4QWO) using DOCK 6.12. Top-performing ligands - were further subjected to 250 ns MD simulations in explicit solvent using GROMACS 2025.2. Structural analyses based on RMSD, radius of gyration, solvent-accessible surface area, residue-wise flexibility, and hydrogen bond persistence analysis. This was followed by MM/GBSA calculations.</p> Results <p> Among the screened compounds, EGCG, Saikosaponin D, ECG, and 10-O-Demethylcephaeline were identified as top candidates. MD simulationsrevealed that 10-O-Demethylcephaeline formed the most stable complex, closely resembling the apo-protein and inducing minimal conformational perturbations. MM/GBSA calculations further identified 10-O-Demethylcephaeline and EGCG as energetically favorable binders, with the former exhibiting a balanced binding profile driven by a low entropic penalty, while EGCG displayed strong enthalpy-driven interactions accompanied by increased structural fluctuations. In contrast, Saikosaponin D and ECG, despite favorable docking scores, showed unfavorable binding free energies due to significant entropic costs.</p> Conclusion <p>Overall, this study highlights the importance of integrating dynamic and thermodynamic analyses with docking-based screening and identifies 10-O-Demethylcephaeline and EGCG as a promising lead candidates for further experimental validation against MPXV A42R.</p> Graphical Abstract <p>DEM and EGCG identified as potential Monkeypox A42R inhibitor via docking, molecular dynamics, and MM/GBSA binding energy analysis</p> <p></p>

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Natural Compounds as Potential Inhibitors of Monkeypox A42R: Docking, Dynamics, and Energetic Insights

  • 期刊论文

  • 发表日期：

    2026年3月27日

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  • Muhammad Hanzla,
  • Ozair Khurram Hashmi,
  • Naureen Mallick,
  • Saltanat Aghayeva,
  • Reaz Uddin

摘要

Background

The resurgence of MonkeyPox Virus (MPXV) and its potential for human-to-human transmission demands the urgent need for novel antiviral agents. Among MPXV’s proteins, the A42R profilin-like protein, implicated in cytoskeletal manipulation and viral pathogenesis, presents an attractive therapeutic target. This study employs an integrative in silico approach to identify natural product-based inhibitors of A42R, utilizing molecular docking, Molecular Dynamics (MD) simulations, and MM/GBSA binding free energy analysis.

Methods

A curated library of natural compounds and secondary metabolites from DrugBank and KNApSAcK databases was screened against the A42R structure (PDB ID: 4QWO) using DOCK 6.12. Top-performing ligands - were further subjected to 250 ns MD simulations in explicit solvent using GROMACS 2025.2. Structural analyses based on RMSD, radius of gyration, solvent-accessible surface area, residue-wise flexibility, and hydrogen bond persistence analysis. This was followed by MM/GBSA calculations.

Results

Among the screened compounds, EGCG, Saikosaponin D, ECG, and 10-O-Demethylcephaeline were identified as top candidates. MD simulationsrevealed that 10-O-Demethylcephaeline formed the most stable complex, closely resembling the apo-protein and inducing minimal conformational perturbations. MM/GBSA calculations further identified 10-O-Demethylcephaeline and EGCG as energetically favorable binders, with the former exhibiting a balanced binding profile driven by a low entropic penalty, while EGCG displayed strong enthalpy-driven interactions accompanied by increased structural fluctuations. In contrast, Saikosaponin D and ECG, despite favorable docking scores, showed unfavorable binding free energies due to significant entropic costs.

Conclusion

Overall, this study highlights the importance of integrating dynamic and thermodynamic analyses with docking-based screening and identifies 10-O-Demethylcephaeline and EGCG as a promising lead candidates for further experimental validation against MPXV A42R.

Graphical Abstract

DEM and EGCG identified as potential Monkeypox A42R inhibitor via docking, molecular dynamics, and MM/GBSA binding energy analysis