Computational Assessment of the Inhibitory Impact of Plectasin: A Fungal Peptide From Pseudoplectania nigrella Against DENV‐2 NS2B‐NS3 Protease

ABSTRACT

Dengue fever (DF) is a worldwide health hazard with no known cure yet. Screenings of synthetic, animal‐derived, and phytocompounds for Dengue virus (DENV) targets have yielded no successful antivirals to date. The present investigation examines medications that act as antagonists of the NS2B‐NS3 protease (NS2B‐NS3 ^Pro ), a potential therapeutic target for DF. Plectasin (PLS) is an antiviral peptide derived from the venom of Pseudoplectania nigrella , a deadly fungus. Previous in vitro studies found that the peptide PLS inhibits DENV‐2 NS2B‐NS3 ^Pro activity. The current in silico research demonstrates the anti‐dengue properties of PLS for the wild‐type (WT) and its two primary mutants (H51N and S135A) of the DENV‐2 NS2B‐NS3 ^Pro in the active‐site region. The peptide toxin (PLS) and the three NS2B‐NS3 ^Pro proteases (WT, H51N, and S135A) were docked by considering their respective active sites. Cluspro‐2 quantifies efficacy, inhibitory consistency, and peptide binding affinity using rigid‐flexible docking. Given the ligand's high binding affinity, docking score, and molecular interaction network, molecular dynamics (MD) simulations and molecular mechanics Generalized‐born surface area (MM‐GBSA)‐based free energy calculations were used to assess the stability of the NS2B/NS3 ^Pro ‐PLS complexes. Anti‐dengue compounds derived from fungal toxins, when screened using computer models, showed promising results. This research is crucial to finding the best treatment for dengue using fungal toxins.