IN-SILICO REPURPOSING OF FDA-APPROVED HEPATITIS C DRUGS, VELPATASVIR AND BOCEPREVIR, AGAINST THE OMICRON VARIANT SPIKE GLYCOPROTEIN

Abstract

The rapid emergence of the SARS-CoV-2 Omicron variant, carrying more than 50 mutations including over 30 within the spike (S) glycoprotein, has challenged existing vaccines and therapeutics. Although several drugs alleviate COVID-19 symptoms, none fully eliminate the virus. Repurposing FDA-approved antivirals provides a fast and cost-effective strategy to identify new therapeutic candidates. Owing to genomic and replication similarities between hepatitis C virus (HCV) and SARS-CoV-2, we assessed the inhibitory potential of two FDA-approved HCV drugs, boceprevir (NS3/4A protease inhibitor) and velpatasvir (NS5A inhibitor), against the Omicron spike using molecular docking. In the absence of an experimentally determined Omicron spike structure, a homology-modeled 3D structure (97.5% sequence identity) was generated and validated through GMQE, QMEAN, Ramachandran, and ERRAT analyses. Active-site residues, including Omicron-specific mutations (LEU365, PRO367, GLN403), were identified via CASTp for docking studies. Both drugs exhibited strong binding affinities, with docking scores of –11.7 kcal/mol (boceprevir) and –12.4 kcal/mol (velpatasvir), and binding free energies of –8.42 and –9.15 kcal/mol, respectively. Interaction analyses revealed stable hydrogen bonding, hydrophobic contacts, and van der Waals interactions with mutational hotspots critical for spike–ACE2 engagement. These findings suggest that velpatasvir and boceprevir may impede Omicron infectivity, warranting further in vitro, in vivo, and clinical validation.