Structure-based repurposing of FDA-approved antiviral drugs targeting hMPV F Protein: Insights from molecular docking and dynamics analysis

Human metapneumovirus (HMPV) is an important cause of respiratory infections, including pneumonia, particularly in infants, older adults, and immunocompromised individuals. Despite its clinical significance, specific antiviral therapies and vaccines against HMPV remain unavailable. In this study, a structure-based computational drug-repurposing strategy was employed to identify FDA-approved drugs targeting the HMPV fusion (F) protein, a key determinant of viral entry and interaction with heparan sulfate (HS). A total of 58 FDA-approved drugs were screened by molecular docking, yielding nine prioritized compounds with docking scores ranging from −9.2 to −5.9 kcal/mol. Among these, Raltegravir, Sofosbuvir, and Efavirenz exhibited the most favorable docking scores of −9.2, −7.0, and −6.7 kcal/mol, respectively, with interactions involving residues within the predicted HS-associated region of the F protein. Based on docking performance and interaction patterns, Raltegravir and Efavirenz were selected for further computational characterization. ADME/T analysis indicated favorable drug-like properties for compounds Raltegravir and Efavirenz within the parameters evaluated. Furthermore, 100 ns molecular dynamics simulations demonstrated comparatively greater structural stability of the Raltegravir–F protein complex, characterized by lower backbone RMSD and residue-level fluctuations and persistent hydrogen-bond interactions compared with the Efavirenz-bound complex. MM-GBSA calculations further supported favorable comparative binding energetic for the prioritized complexes, while density functional theory (DFT) calculations provided additional insight into their electronic properties. Collectively, the integrated computational analyses identify Raltegravir as a computationally prioritized candidate for further investigation against HMPV F protein. However, these findings represent theoretical predictions and require experimental validation through biochemical, cellular, and in vivo studies to determine their antiviral activity and therapeutic potential.