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Purpose <p>Ebolavirus, a deadly pathogen prevalent in West and Equatorial Africa, causes severe hemorrhagic fever, immune suppression, and multi-organ dysfunction. Its VP24 protein disrupts the host immune response by binding to karyopherin-α (KPNA), preventing the nuclear transport of STAT1, a key factor in interferon signaling, thereby impairing antiviral defenses. Targeting VP24 is crucial to counteract immune evasion.</p> Methods <p>A structure-based virtual screening of 954 phytocompounds from the African Natural Product Database was performed against the VP24 binding interface. The top candidates were evaluated through induced-fit docking, pharmacokinetic and toxicity profiling, followed by 400 ns molecular dynamics (MD) simulations and binding free energy calculations.</p> Results <p>The virtual drug screening identified four lead compounds with high specificity and notable docking scores such as EA_0065 (-7.54&#xa0;kcal/mol), SA_146 (-6.90&#xa0;kcal/mol), WA_0114 (-6.40&#xa0;kcal/mol), and SA_0143 (-6.32&#xa0;kcal/mol). MD simulations revealed that all complexes maintained stable conformations throughout 400 ns, exhibiting minimal structural deviations (RMSD 1.5-2.0 Å) and consistent compactness, confirming robust and stable binding. The recorded binding free energies of EA_0065-VP24, SA_146-VP24, WA_0114-VP24, and SA_0143_VP24 complexes were − 39.49 ± 0.41&#xa0;kcal/mol, -25.57 ± 0.33&#xa0;kcal/mol, -27.60 ± 0.64&#xa0;kcal/mol, and − 12.31 ± 0.40&#xa0;kcal/mol respectively which further validated the stability of complexes. The favorable pharmacokinetics properties such no potential toxicities, high water solubility and effective intestinal absorption further confirmed the potency of lead compounds.</p> Conclusion <p>In conclusion, these findings underscore the potential of the identified compounds as therapeutic agents to restore antiviral immunity by targeting Ebolavirus VP24-mediated immune evasion mechanisms.</p>

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Targeting the VP24-Karyopherin-α Interface With Phytocompounds: A Structure-Based Molecular Screening and Dynamic Simulation Approach to Rescue Immune Responses Against Ebola Virus

  • 期刊论文

  • 发表日期：

    2026年2月3日

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  • Mohammed A. Alshehri,
  • Mohammed Alissa,
  • Muhammad Suleman

摘要

Purpose

Ebolavirus, a deadly pathogen prevalent in West and Equatorial Africa, causes severe hemorrhagic fever, immune suppression, and multi-organ dysfunction. Its VP24 protein disrupts the host immune response by binding to karyopherin-α (KPNA), preventing the nuclear transport of STAT1, a key factor in interferon signaling, thereby impairing antiviral defenses. Targeting VP24 is crucial to counteract immune evasion.

Methods

A structure-based virtual screening of 954 phytocompounds from the African Natural Product Database was performed against the VP24 binding interface. The top candidates were evaluated through induced-fit docking, pharmacokinetic and toxicity profiling, followed by 400 ns molecular dynamics (MD) simulations and binding free energy calculations.

Results

The virtual drug screening identified four lead compounds with high specificity and notable docking scores such as EA_0065 (-7.54 kcal/mol), SA_146 (-6.90 kcal/mol), WA_0114 (-6.40 kcal/mol), and SA_0143 (-6.32 kcal/mol). MD simulations revealed that all complexes maintained stable conformations throughout 400 ns, exhibiting minimal structural deviations (RMSD 1.5-2.0 Å) and consistent compactness, confirming robust and stable binding. The recorded binding free energies of EA_0065-VP24, SA_146-VP24, WA_0114-VP24, and SA_0143_VP24 complexes were − 39.49 ± 0.41 kcal/mol, -25.57 ± 0.33 kcal/mol, -27.60 ± 0.64 kcal/mol, and − 12.31 ± 0.40 kcal/mol respectively which further validated the stability of complexes. The favorable pharmacokinetics properties such no potential toxicities, high water solubility and effective intestinal absorption further confirmed the potency of lead compounds.

Conclusion

In conclusion, these findings underscore the potential of the identified compounds as therapeutic agents to restore antiviral immunity by targeting Ebolavirus VP24-mediated immune evasion mechanisms.