Abstract
Oropouche virus (OROV), an emerging orthobunyavirus of increasing public health concern in the Americas, currently lacks approved antiviral therapies. In this study, we employed a structure-based in silico approach to identify natural antiviral scaffolds capable of targeting the Gc glycoprotein, a class II fusion protein essential for host membrane fusion and viral entry. A library of 537 plant-derived compounds was screened against the Gc head domain (PDB ID: 6H3X) through molecular docking and redocking, followed by 100-nanosecond molecular dynamics simulations, MM-PBSA free energy calculations, and ADMET profiling. Curcumin and Berberine emerged as standout candidates. Curcumin demonstrated a balanced profile, with stable binding (-38.14 kcal/mol), low backbone RMSD (1.82 Å), and consistent radius of gyration (Rg ~ 18.8 Å), suggesting strong conformational stability and compactness of the protein-ligand complex. Berberine exhibited the most favorable binding energy (-13.10 kcal/mol) and retained dynamic stability (RMSD 1.86 Å; Rg ~ 19.0 Å), though accompanied by predicted cytotoxicity that may require structural refinement. Both compounds induced reduced residue-level fluctuations (RMSF < 2.5 Å) in functionally critical regions of the Gc protein, consistent with a mechanism of action that involves stabilization of the prefusion conformation and interference with the structural transitions required for viral entry. These findings identify curcumin and berberine as promising scaffolds for anti-OROV drug development and offer a rational foundation for future experimental validation targeting viral fusion mechanisms.