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<p>The RNA- directed RNA polymerase (RdRp) of Ebola virus (EBOV) represents a highly validated and druggable target for the development of novel anti-EBOV therapeutics. This study aimed to identify plant-derived compounds capable of inhibiting EBOV RdRp and to characterize their binding mechanisms through an integrated computational approach encompassing pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulations. From the Natural Products Activity and Species Source (NPASS) database, 37 phytochemicals exhibiting stronger predicted binding affinity than the reference inhibitor suramin were prioritized. Docking analysis revealed that the top three hits (NPC72350, NPC136008, and NPC217491) bind tightly within the NTP entry channel of EBOV RdRp, sterically obstructing NTP access to the catalytic active site and thereby suppressing polymerase activity. Consistent with this, 200-ns MD simulations demonstrated enhanced structural stability of the three hit-RdRp complexes and confirmed sustained occupancy of the compounds within the NTP entry channel. Network pharmacology analysis further indicated that these phytochemicals not only directly target EBOV RdRp but also modulate host immune responses and disrupt critical virus-host interactions. Collectively, these findings provide a mechanistically grounded foundation for the rational design of next-generation EBOV RdRp inhibitors.</p>

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Computational Screening Novel Inhibitors from Plant-Derived Natural Products Against RNA-Directed RNA Polymerase of Ebola Virus

  • 期刊论文

  • 发表日期：

    2026年6月14日

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  • Shaohua Xu,
  • Huicheng Yuan

摘要

The RNA- directed RNA polymerase (RdRp) of Ebola virus (EBOV) represents a highly validated and druggable target for the development of novel anti-EBOV therapeutics. This study aimed to identify plant-derived compounds capable of inhibiting EBOV RdRp and to characterize their binding mechanisms through an integrated computational approach encompassing pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulations. From the Natural Products Activity and Species Source (NPASS) database, 37 phytochemicals exhibiting stronger predicted binding affinity than the reference inhibitor suramin were prioritized. Docking analysis revealed that the top three hits (NPC72350, NPC136008, and NPC217491) bind tightly within the NTP entry channel of EBOV RdRp, sterically obstructing NTP access to the catalytic active site and thereby suppressing polymerase activity. Consistent with this, 200-ns MD simulations demonstrated enhanced structural stability of the three hit-RdRp complexes and confirmed sustained occupancy of the compounds within the NTP entry channel. Network pharmacology analysis further indicated that these phytochemicals not only directly target EBOV RdRp but also modulate host immune responses and disrupt critical virus-host interactions. Collectively, these findings provide a mechanistically grounded foundation for the rational design of next-generation EBOV RdRp inhibitors.