Repurposing Metal‐Based Therapeutics for Human Metapneumovirus (HMPV): An Integrative Computational Approach

Human metapneumovirus (HMPV) is a respiratory pathogen of global concern, particularly affecting infants, the elderly, and immunocompromised individuals. Despite its prevalence, no targeted antiviral therapies are currently approved. In this study, we employed a structure-guided computational strategy to repurpose clinically approved metal-based drugs as potential HMPV inhibitors. A curated chemical library was screened against the HMPV fusion protein (PDB ID: 5WB0) using high-accuracy molecular docking, followed by molecular dynamics (MD) simulations (2000 ns), binding free energy calculations, and pharmacophore modeling. Top-ranked compounds—Auranofin, silver sulfadiazine, and gallium nitrate—exhibited superior binding affinities (ΔG_binding: −68.5 to −62.7 kcal/mol), stable protein–ligand complexes (RMSD: 2.1–2.4 Å), and consistent interaction profiles when benchmarked against known antivirals ribavirin and favipiravir. Quantum chemical descriptors derived from density functional theory (DFT) and molecular electrostatic potential (MESP) mapping confirmed their favorable electronic properties, including optimal HOMO–LUMO gaps and total energy stability. Furthermore, ADMET predictions revealed acceptable oral bioavailability, low predicted toxicity, and renal clearance profiles, though known risks such as gallium accumulation were acknowledged. This integrative study highlights the potential of repurposed metallodrugs as novel anti-HMPV agents, offering a rational and cost-effective path toward therapeutic advancement.