Structural insights into natural compound inhibitors of the human metapneumovirus nucleocapsid protein via molecular dynamics and free energy landscape analyses

Human Metapneumovirus (HMPV) is a major contributor to acute respiratory tract infections, particularly affecting children, the elderly, and immunocompromised individuals. Despite its global prevalence, no specific antiviral treatments or vaccines are available, highlighting the urgent need for effective therapeutic interventions. This study utilized a comprehensive computational drug discovery approach to identify potential inhibitors targeting the highly conserved nucleocapsid (N) protein of HMPV, a crucial component in viral replication and transcription. A virtual screening of 1,227 natural compounds from the NP-lib database was performed, identifying MOLPORT-001-742-110, MOLPORT-001-812-855, and MOLPORT-001-740-100 as the top candidates based on their docking scores and binding energies. The initial results were validated through re-docking, molecular interaction analysis, and molecular dynamics (MD) simulations. MOLPORT-001-742-110 demonstrated the highest stability with minimal deviations in Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) analyses, as well as a well-defined low-energy conformation in the Free Energy Landscape (FEL). Key hydrogen bonds and hydrophobic interactions were retained, reinforcing its strong binding affinity. Principal Component Analysis (PCA) and superimposition studies further supported the stability and adaptability of these compounds within the binding site. Comparative analyses with the control compound confirmed the superior inhibitory potential of the selected ligands, particularly MOLPORT-001-742-110. This study underscores the utility of computational approaches in identifying natural product-based inhibitors and provides a foundation for experimental validation and development of antiviral therapies against HMPV.