Disruption of Marburg virus VP35–dsRNA interactions by natural compounds: Insights from molecular simulations

Abstract

Marburg virus (MarV) hemorrhagic fever is a highly lethal disease endemic to parts of Africa, with outbreaks reporting up to 90% mortality. The virus’s virulence is largely attributed to VP35, a multifunctional protein that suppresses host immunity through interferon antagonism. Currently, no approved treatments exist, although nucleoside analogues such as Favipiravir and Remdesivir are under investigation. Nevertheless, the search for alternative chemical scaffolds remains critical, particularly those derived from natural products, a rich reservoir of lead compounds against a variety of pathogens. The present study employs a multistage molecular simulation cascade to identify potential VP35 inhibitors from a curated African natural compound library. Structure-based virtual screening against the VP35–dsRNA complex, identified 134 compounds with superior docking scores ( ≥ − 7 . 0 k c a l m o l − 1 ). Pharmacokinetic and toxicity filtering narrowed the list to 15 candidates, which underwent triplicate 50 ns molecular dynamics simulations at 300 K . Binding free energies were computed using MM-PBSA and MM-GBSA methods to re-rank ligands efficacy. Seven top-performing compounds then underwent extended 500 ns simulations, followed by principal component and inter-chain quantitative analyses, revealing disruption of the VP35 RNA-binding domain. Density Functional Theory calculations suggested favorable electronic properties, including high reactivity and electrophilicity, which further underscore the inhibitory potential of the studied compounds. Ultimately, SA260 emerged as the most promising inhibitor, followed by SA394, EA636, CO1641, NA1411, CO1627, and CO2049. Seven additional compounds showed consistent performances across all analyses. These results highlight natural compounds with predicted potential to disrupt VP35–dsRNA interactions, restore immune signaling, and serve as leads for antiviral drug development against MarV and related filoviruses.