ArticlePloS one2026
Mechanistic inhibition of herpes simplex virus-1 UL21 immune-evasion function by natural-product scaffolds: A multi-tier docking, dynamics, and energetic profiling approach.
Article in PloS one, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Alpha-herpesviruses, particularly herpes simplex virus type 1 (HSV-1), establish lifelong latency and employ multiple strategies to evade host immunity, thereby sustaining infection. A key mediator of this immune evasion is the viral tegument protein, unique long 21 (UL21), which disrupts the host cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway and suppresses antiviral type-I interferon responses, facilitating viral replication. Despite its important role in HSV-1 pathogenesis, UL21 remains an underexplored therapeutic target. This study aimed to identify natural-product scaffolds capable of targeting the UL21 N-terminal domain and potentially interfering with UL21-mediated immune evasion. Using comprehensive virtual screening of East and South African natural-product libraries, we employed a multi-tier computational workflow comprising molecular docking, molecular dynamics (MD) simulations, and binding free-energy calculations. 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.
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