Marine bioactive molecules as potential antiviral agents against HMPV key proteins: An integrated machine learning based in-silico approach

Human Metapneumo Virus (HMPV), a common respiratory pathogen, is a major health concern, especially for children, elderly, and immunocompromised individuals. Currently there are no approved antivirals or vaccines available for the treatment, this study used an integrated in silico approach to find possible marine-derived inhibitors that target three essential viral proteins, namely, fusion glycoprotein (F protein), RNA-dependent RNA polymerase (RdRp), and nucleoprotein-RNA (N-RNA) complex. After screening a curated library of 46,367 marine products from the CMNPD, 14,097 compounds satisfied drug-likeness standards based on ADME profiling with QikProp. Top candidates CMPD40601 (F protein, docking score: −6.856 kcal/mol), CMPD20129 (RdRp, −5.976 kcal/mol), and CMPD46444 (N-RNA, −6.000 kcal/mol) were found by high-throughput virtual screening (HTVS), which was followed by SP and XP molecular docking. Lys 254 and Asp 336 (F protein), Arg 556 and Lys 19 (RdRp), and Arg 341 (N-RNA) were important interactions. Variable electronic stability was shown by DFT calculations, which showed HOMO-LUMO energy gaps of 5.85 eV (CMPD46444), 5.00 eV (CMPD40601), and 4.79 eV (CMPD20129). Under physiological conditions, these candidates showed robust binding in molecular dynamics simulations (100 ns), with CMPD20129 exhibiting strong residue-level interaction stability. Additional evidence for their suitability as drug leads came from fingerprint analysis and metabolism prediction. These results demonstrate the unrealized potential of marine products in the search for antiviral drugs and suggest that CMPD40601 be considered as a promising lead against HMPV F protein for further preclinical testing.