Molecular docking, molecular dynamic simulation, and ADME analysis of Moringa oleifera phytochemicals targeting NS5 protein: towards the development of novel anti-dengue therapeutics.

OBJECTIVES: Dengue virus (DENV), a single-stranded RNA virus from the Flaviviridae family, causes viral hemorrhagic fever and poses a global health threat due to limited diagnostics, treatments, and vaccines. The conserved NS5 protein, crucial for DENV replication, is a promising antiviral target. Antibody-dependent enhancement (ADE) complicates immunity, as serotype-specific antibodies may worsen infection. Moringa oleifera, rich in antiviral phytochemicals, shows potential as a DENV inhibitor by targeting proteomic, transcriptomic, and metabolomic pathways.

METHODS: This study employed molecular docking with 3D PubChem structures of bioactive compounds of M. oleifera to evaluate the binding affinity with DENV-2 NS5 proteins (PDB ID: 6KR2) using AutoDock Vina, and binding modes were analyzed using Discovery Studio. Further drug-likeness, oral bioavailability, ADME, and toxicity profiles were analyzed using SwissADME, ADMETSaR, and ADMETlab 3.0 web server. Complexes were subjected to molecular dynamics simulation (MDS) analysis using Desmond Schrodinger v2019.

RESULTS: Among the screened compounds, rhamnopyranosyl vincosamide (-9.0 kcal/mol), luteoxanthin (-8.6 kcal/mol), and luteolin (-8.3 kcal/mol) exhibited the most stable interactions and were further analyzed through molecular dynamics (MD) simulations. The results revealed that these phytochemicals interact with NS5 active-site residues, demonstrating significant inhibitory potential.

CONCLUSIONS: The study suggests that M. oleifera phytochemicals hold promise as DENV-2 NS5 inhibitors with minimal toxicity and favorable pharmacokinetic properties. These findings provide a strong foundation for further clinical investigations, potentially contributing to developing novel anti-dengue therapeutics.