Repurposing FDA‐Approved Antiviral Drugs Against Human Metapneumovirus Fusion Protein: Integrated Docking, Molecular Dynamics, and Quantum Chemical Insights

Abstract

Human metapneumovirus (HMPV) is a major respiratory pathogen lacking an approved targeted antiviral therapy. This study aimed to identify FDA‐approved antiviral drugs targeting the prefusion HMPV fusion glycoprotein using an integrated computational framework. Fourteen FDA‐approved antiviral drugs and two control compounds were evaluated against the HMPV fusion glycoprotein (PDB ID: 5WB0) using virtual screening, molecular docking, 2000 ns molecular dynamics (MD) simulations, MM/PBSA binding free‐energy calculations, hydrogen‐bond occupancy and dynamic cross‐correlation matrix (DCCM) analyses, density functional theory (DFT), molecular electrostatic potential (MESP) mapping, pharmacophore modeling, and ADMET prediction. Remdesivir and Peramivir exhibited the highest docking affinities (−9.5 and −9.2 kcal mol − 1 , respectively) and formed highly stable protein–ligand complexes throughout the molecular dynamics (MD) simulations. Remdesivir showed minimal structural deviation (RMSD: 0.20 ± 0.02 nm), persistent hydrogen‐bond occupancy, favorable residue correlation patterns, and the most favorable MM/PBSA binding free energy (−45.30 ± 2.00 kcal mol− 1 ). DFT and MESP analyses demonstrated favorable electronic properties, while pharmacophore mapping and ADMET prediction supported strong target recognition, high intestinal absorption, and low predicted toxicity. Integrated computational analyses consistently prioritize Remdesivir and Peramivir as promising candidates for HMPV drug repurposing, providing a robust framework for future experimental validation and antiviral drug discovery.