Repositioning antiviral phytoconstituents as broad-spectrum inhibitors of influenza A neuraminidase and human metapneumovirus fusion protein.

Viral respiratory infections still exist as a major global health concern. Influenza A viruses and human metapneumoviruses are among the main pathogens responsible for infections that can progress to severe acute respiratory forms. Despite the availability of certain therapeutic options, the need for effective treatment remains an issue. The exploration of innovative approaches based on medicinal plants, capable of simultaneously targeting several viruses, represents a promising strategic option for limiting the viral activity of these pathogens. In this work, an integrated computational workflow combining molecular docking, ADMET prediction, molecular dynamics (MD) simulations, and MM-PBSA binding free-energy analysis was applied to evaluate previously reported antiviral phytoconstituents for their broad-spectrum antiviral potential by simultaneously targeting influenza A virus neuraminidase (NA) (PDB ID: 2HT7) and the human metapneumovirus (HMPV) fusion protein (F) (PDB ID: 7SEJ). Molecular docking analyses identified 37 phytoconstituents with favorable multi-target binding affinities toward both NA and F proteins, exhibiting more favorable predicted binding energies than the reference compounds oseltamivir and ribavirin. In addition, ADMET prediction, including bioavailability assessment and analysis of pharmacokinetic and toxicological properties, identified several compounds with favorable profiles, notably compounds E10, M294, M329, C11, C5, and M274. MD simulations followed by MM-PBSA binding free-energy calculations further validated the stability and binding behavior of the highest-ranked protein-ligand complexes identified through the sequential screening workflow. Overall, compounds M294 and C11 emerged as the most promising broad-spectrum antiviral lead candidates against both influenza A NA and HMPV F protein. Nevertheless, these findings are based on computational predictions and require confirmation through in vitro antiviral assays followed by in vivo studies.