<p>Supporting files.</p>

Four compounds, Saundersioside C, kaempferol 3,7,4′-tri-O-β-glucoside, soyasaponin II, and OSW‑1, emerged as promising UL21-binding candidates with favorable docking scores and stable interaction profiles. Docking scores for saundersioside C, kaempferol 3,7,4′-tri-O-β-glucoside, soyasaponin II, and OSW-1 were −9.05, −8.94 kcal/mol, −7.45 kcal/mol, and −7.30 kcal/mol, respectively. Molecular dynamics (MD) trajectory analyses demonstrated stable conformational behavior as indicated by consistent root mean square deviation (RMSD), limited structural fluctuations, and persistent structural compactness.

Total binding free-energy calculations further identified kaempferol 3,7,4′-tri-O-β-glucoside (−40.9 kcal/mol MM/GBSA; −33.9 kcal/mol MM/PBSA) as the compound with the most favorable predicted binding affinity toward UL21. Collectively, these findings identify natural-product scaffolds with high potential to modulate UL21-mediated immune suppression, with kaempferol 3,7,4′-tri-O-β-glucoside emerging as the most promising candidate.

The findings provide a foundation for experimental validation and future antiviral drug development targeting HSV-1.</p></div>