Inhibiting viral entry of bat-derived coronavirus HKU5-CoV-2: Targeting spike protein S1 subunit with FDA-approved antivirals-A structural dynamics and energetics study.

The ongoing risk of zoonotic transmission from bat-derived coronaviruses underscores the urgent need for broad-spectrum antiviral strategies. In this study, we investigate the potential of Food and Drug Administration (FDA)-approved antiviral drugs to inhibit the S1 C-terminal domain of the spike protein from HKU5-CoV-2, a Merbecovirus closely related to Middle East Respiratory Syndrome Coronavirus (MERS-CoV). A structure-based virtual screening approach was employed, followed by 3000 ns molecular dynamics (MD) simulations and binding free energy estimation using MM-PBSA analysis. Among the screened compounds, Ombitasvir/Paritaprevir/Ritonavir, Acyclovir, and Ribavirin demonstrated the highest docking binding affinities (e.g., -9.34 kcal/mol), surpassing benchmark controls like Remdesivir (-9.80 kcal/mol) and Ribavirin (-9.75 kcal/mol). Subsequent MM-PBSA analysis revealed favorable dynamic binding energies, with Ombitasvir/Paritaprevir/Ritonavir exhibiting the most stable interaction at -56.37 kcal/mol. Key MD metrics-including root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), hydrogen bonding (H-bonding), and ligand stability-supported the robustness of these drug-protein complexes. Quantum chemical calculations via Density Functional Theory (DFT) further confirmed the high reactivity of Ombitasvir/Paritaprevir/Ritonavir, with a low Highest Occupied Molecular Orbital (HOMO)- Lowest Unoccupied Molecular Orbital (LUMO) gap (0.020 eV) and strong electrophilicity. Molecular electrostatic potential (MESP) mapping provided insight into electrostatic complementarity at the binding interface. Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling revealed favorable drug-likeness, though predicted hepatotoxicity (Ombitasvir/Paritaprevir/Ritonavir) and mutagenicity (Ribavirin) warrant further preclinical evaluation. The targeted S1 domain is structurally conserved and surface-accessible, suggesting high potential for cross-protective intervention. This multi-tiered computational framework highlights repurposed antivirals with promising inhibitory activity against a potentially emergent bat coronavirus, and lays the foundation for future in vitro and in vivo validation. Please use this abstract for the final version publication.