Uncovering potent natural phytochemicals targeting SARS-COV-2 spike protein variants: molecular dynamics insights.

SARS-CoV-2 remains a critical global health concern due to its high transmissibility, evolving variants, and the absence of a universally effective treatment. Phytocompounds, known for their antiviral, anti-inflammatory, and immunomodulatory properties, continue to be explored as potential therapeutic agents. This study evaluated 20 phytocompounds and four approved antiviral drugs, Remdesivir, Favipiravir, Hydroxychloroquine, and Ivermectin, against nine SARS-CoV-2 spike glycoprotein structures, including five wild-type and four variants (Alpha, Beta, Delta, and Omicron). Molecular docking using two software platforms identified ursolic acid, betulinic acid, β-sitosterol, and ivermectin as top candidates, with binding affinities ranging from - 6.7 to - 9.6 kcal/mol. These compounds also displayed favorable pharmacokinetic properties and druggability. 100 ns molecular dynamics simulations were performed on the highest-affinity complexes to assess stability. Betulinic acid and β-sitosterol demonstrated stable binding interactions, with low RMSD values (~ 0.2-0.3 nm) and consistent hydrogen bonding (1-3 bonds), suggesting structural stability. In contrast, ursolic acid and ivermectin showed unstable binding and higher structural fluctuations during simulation. Overall, the study highlights betulinic acid and β-sitosterol as presumptive SARS-CoV-2 inhibitors, warranting further experimental validation through in vitro and in vivo studies to confirm their therapeutic potential.