Decoding potential host protein targets against Flaviviridae using protein-protein interaction network

Flaviviridae family comprises some of the most vulnerable viruses known for causing widespread outbreaks, high mortality rates, and severe long-term health complications in humans. Viruses like Dengue (DENV), Zika (ZIKV) and Hepatitis C (HCV) are endemic across the globe, especially in tropical and subtropical regions, infecting multiple tissues and leading to significant health crises. Investigating virus-host interactions across tissues can reveal tissue-specific drug targets and aid antiviral drug repurposing. In this study, we employed a multi-step computational approach to construct a comprehensive virus-human interactome by integrating virus-host protein-protein interactions (PPIs) with tissue-specific gene expression profiles to study key protein targets associated with Flaviviridae infections. Mapping drug-target predictions revealed druggable proteins - CCNA2 in peripheral blood mononuclear cells (PBMC) and EIF2S2, CDK7 and CARS in the liver, with Tamoxifen, Sirolimus, Entrectinib and L-cysteine as potential repurposable drugs, respectively. Further protein-ligand docking and molecular dynamics (MD) simulations were conducted to assess the stability of the complexes. These findings highlight common druggable human targets exploited by DENV, ZIKV and HCV, providing a foundation for broad-spectrum antiviral therapies. By focusing on shared host pathways and targets in viral replication, we propose promising drug candidates, supporting the development of unified therapeutic strategies against Flaviviridae viruses.