{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T18:05:18Z","timestamp":1789581918727,"version":"build-2803163510"},"reference-count":57,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Qatar Research, Development, and Innovation (QRDI) Council","award":["PPM-08-0220-250062"],"award-info":[{"award-number":["PPM-08-0220-250062"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>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\u2032-tri-O-\u03b2-glucoside, soyasaponin II, and OSW\u20111, emerged as promising UL21-binding candidates with favorable docking scores and stable interaction profiles. Docking scores for saundersioside C, kaempferol 3,7,4\u2032-tri-O-\u03b2-glucoside, soyasaponin II, and OSW-1 were \u22129.05, \u22128.94 kcal\/mol, \u22127.45 kcal\/mol, and \u22127.30 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\u2032-tri-O-\u03b2-glucoside (\u221240.9 kcal\/mol MM\/GBSA; \u221233.9 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\u2032-tri-O-\u03b2-glucoside emerging as the most promising candidate. The findings provide a foundation for experimental validation and future antiviral drug development targeting HSV-1.<\/jats:p>","DOI":"10.1371\/journal.pone.0355499","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:54:02Z","timestamp":1789581242000},"page":"e0355499","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic inhibition of herpes simplex virus-1 UL21 immune-evasion function by natural-product scaffolds: A multi-tier docking, dynamics, and energetic profiling approach"],"prefix":"10.1371","volume":"21","author":[{"given":"Muhammad","family":"Suleman","sequence":"first","affiliation":[{"name":"Biomedical Research Center (BRC), QU Health, Qatar University","place":["Doha, Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imtiaz","family":"Ali","sequence":"additional","affiliation":[{"name":"Center for Biotechnology and 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