Molecular Simulations driven Identification of Natural Compounds as Marburg Virus VP35 Inhibitors

Marburg virus (Marv) hemorrhagic fever is a sporadic and highly lethal disease endemic to several African countries, with recent outbreaks showing up to 90% mortality. The virus’s pathogenicity is largely mediated by the multifunctional protein VP35, which enables immune evasion through interferon antagonism. Currently, there are no approved treatments for MarV infections, though various antiviral interventions, including small-molecule inhibitors like Favipiravir, are under development. This study employs a multi-scale molecular simulation approach to identify potential inhibitors of Marv VP35 from an African natural compounds library. Structure-based virtual screening was performed to identify potent hits, with Favipiravir as the reference compound. A total of 134 molecules outperformed Favipiravir in docking scores (at least -1.2 kcal/mol), and these were further evaluated for toxicity and pharmacokinetics. Fifteen compounds were shortlisted for molecular dynamics simulations over 50 nanoseconds at 300 ° K to account for receptor flexibility and biological conditions. All shortlisted compounds demonstrated greater stability than Favipiravir, except compound CO921. Binding free energies were calculated using MM-PBSA/MM-GBSA methods, leading to the re-ranking of the compounds. Ultimately, compound SA260, followed by NA1411, EA636, SA394, and CO1641 emerged as the most promising inhibitors of Marv VP35. Additionally, six other compounds were identified as potential alternatives. The findings suggest these compounds may effectively antagonize dsRNA binding, leading to VP35 inhibition and subsequent Marv immunosuppression. This study provides a critical step toward the discovery of antiviral agents for Marv and other filoviruses.