In silico drug repurposing targeting fusion and nucleoprotein of human metapneumovirus: A step toward pandemic preparedness.

Abstract

Background: Human metapneumovirus (HMPV) is an emerging respiratory pathogen affecting children, elderly individuals, and immunocompromised patients. Despite its disease burden, no antiviral treatment has been approved to date.

Objective: The present study aimed to identify the Food and Drug Administration-approved drugs with potential for repurposing against HMPV by targeting its key structural proteins-fusion (F) and nucleoprotein (N).

Materials and methods: The crystallographic structures of HMPV fusion (Protein Data Bank [PDB] ID: 5WB0) and nucleoprotein (PDB ID: 5FVD) were retrieved, validated, and subjected to molecular docking. Ligands with favorable binding scores were further evaluated using molecular dynamics simulations and binding-free-energy calculations. Pharmacokinetic and toxicity profiles were predicted to assess their translational viability.

Results: For the fusion protein, rutin, carbetocin, and acarbose showed strong binding affinities and stable molecular interactions. For the nucleoprotein, mobocertinib, lapatinib, and levetiracetam emerged as top candidates, with mobocertinib showing the most favorable binding energy. Among all, levetiracetam displayed the most drug-like characteristics, including high gastrointestinal absorption, no major cytochrome P450 inhibition, and no violations of Lipinski's rule.

Conclusion: The study highlights mobocertinib, rutin, and levetiracetam as promising repurposed drugs against HMPV. While mobocertinib exhibited the strongest predicted binding affinity, levetiracetam demonstrated the best pharmacokinetic profile, making it a particularly viable candidate for further experimental validation. These results validate the usefulness of in silico drug repurposing in addressing unmet antiviral needs and warrant preclinical studies to evaluate therapeutic efficacy.