Molecular docking insights of Nigella sativa compounds as potential antiviral inhibitory agents against the replication-machinery proteins VPg and RdRP in rabbit hemorrhagic disease virus (RHDV)

The Rabbit Hemorrhagic Disease Virus (RHDV) represents a significant threat to rabbit populations globally, affecting both wild and domesticated rabbits, with mortality rates ranging from 50% to 90%. Despite its severity, there is currently no specific treatment available for RHDV. This study investigates the potential of natural compounds derived from Nigella sativa as antiviral agents against RHDV. Molecular docking analysis was conducted to explore the interaction between eleven compounds from Nigella sativa and the two key proteins of RHDV, viral protein genome-linked (VPg) and RNA-dependent RNA polymerase (RdRP), as key proteins involved in viral replication. Explicit-solvent MD (100 ns, 310 K) was performed for four top complexes (VPg/RdRP with nigellidine and dithymoquinone), tracking backbone/ligand RMSD, radius of gyration, H-bond counts, and per-residue RMSF, with equilibrated frames analyzed by PCA and MM-GBSA. The results revealed successful docking of all compounds from Nigella sativa to both VPg and RdRP proteins. From Nigella sativa compounds, Nigellidine and Dithymoquinone displayed strong interactions with VPg and RdRP and formed various hydrogen bonds and hydrophobic interactions, indicating their potential as inhibitors of viral replication. Interestingly, all ligands demonstrated favorable drug-likeness properties, adhering to Lipinski's Rule of Five and exhibiting desirable pharmacokinetic profiles. Thymohydroquinone and nigellidine displayed the highest lipophilicity, suggesting their potential for efficient tissue penetration and distribution. Complexes remained stable and retained poses, with reduced pocket flexibility, favorable MM-GBSA ΔG_bind, and tighter PCA clustering-supporting sustained binding and pocket stabilization. These findings suggest that compounds from Nigella sativa show promise as natural antiviral agents against RHDV. Nevertheless, additional experimental validation through in vitro and in vivo studies is essential to confirm the effectiveness and safety of these compounds for treating RHDV infection.