Systems Biology-Driven Discovery of Host-Targeted Therapeutics for Oropouche Virus: Integrating Network Pharmacology, Molecular Docking, and Drug Repurposing.

Oropouche virus (OROV), part of the Peribunyaviridae family, is an emerging pathogen causing Oropouche fever, a febrile illness endemic in South and Central America. Transmitted primarily through midge bites (), OROV has no specific antiviral treatment or vaccine. This study aims to identify host-targeted therapeutics against OROV using computational approaches, offering a potential strategy for sustainable antiviral drug discovery. Virus-associated host targets were identified using the OMIM and GeneCards databases. The Enrichr and DSigDB platforms were used for drug prediction, filtering compounds based on Lipinski's rule for drug likeness. A protein-protein interaction (PPI) network analysis was conducted using the STRING database and Cytoscape 3.10.3 software. Four key host targets-IL10, FASLG, PTPRC, and FCGR3A-were prioritized based on their roles in immune modulation and OROV pathogenesis. Molecular docking simulations were performed using the PyRx software to evaluate the binding affinities of selected small-molecule inhibitors-Acetohexamide, Deptropine, Methotrexate, Retinoic Acid, and 3-Azido-3-deoxythymidine-against the identified targets. The PPI network analysis highlighted immune-mediated pathways such as Fc-gamma receptor signaling, cytokine control, and T-cell receptor signaling as critical intervention points. Molecular docking revealed strong binding affinities between the selected compounds and the prioritized targets, suggesting their potential efficacy as host-targeting antiviral candidates. Acetohexamide and Deptropine showed strong binding to multiple targets, indicating broad-spectrum antiviral potential. Further in vitro and in vivo validations are needed to confirm these findings and translate them into clinically relevant treatments. This study highlights the potential of using computational approaches to identify host-targeted therapeutics for Oropouche virus (OROV). By targeting key host proteins involved in immune modulation-IL10, FASLG, PTPRC, and FCGR3A-the selected compounds, Acetohexamide and Deptropine, demonstrate strong binding affinities, suggesting their potential as broad-spectrum antiviral candidates. Further experimental validation is needed to confirm their efficacy and potential for clinical application, offering a promising strategy for sustainable antiviral drug discovery.