Virtual Screening of Marine Natural Products Targeting the F Protein for Anti-RSV Drug Discovery

Respiratory syncytial virus (RSV) poses a substantial global health burden, particularly in infants and the elderly. The fusion (F) protein is a key therapeutic target for inhibiting RSV entry. In this study, we performed a structure-based virtual screening of the Comprehensive Marine Natural Products Database (CMNPD) to discover novel anti-RSV agents targeting the prefusion F protein trimer. Screening of 31,561 compounds via molecular docking, followed by stringent ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling and MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) binding free energy calculations, identified 11 promising candidates. Among these, manzamine alkaloids exhibited the most favorable docking scores (as low as -13.3 kcal/mol) and promising Ligand Efficiency (LE) values. These molecules primarily interact with conserved hydrophobic residues (Phe140, Phe488) through hydrophobic interactions, π-stacking, and electrostatic forces. Our study highlights marine natural products, especially manzamine alkaloids, as promising leads for the development of novel, orally bioavailable RSV fusion inhibitors, potentially offering avenues to overcome existing drug resistance. However, these computational findings require in vitro validation to confirm efficacy.