Mechanistic inhibition of herpes simplex virus-1 UL21 immune-evasion function by natural-product scaffolds: A multi-tier docking, dynamics, and energetic profiling approach
6 affiliations
- 1Biomedical Research Center (BRC), QU Health, Qatar University, Doha, Qatar
- 2Center for Biotechnology and Microbiology, University of Swat, Swat, Pakistan
- 3School of Chemical Sciences, Universiti Sains Malaysia, Gelugor, Penang, Malaysia
- 4Department of Medical Laboratory Technology, Faculty of Rehabilitation and Allied Health Sciences, Riphah International University, Islamabad, Pakistan
- 5Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
- 6Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
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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BibTeX
@article{suleman2026mechanistic,
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}},
author = {Muhammad Suleman and Imtiaz Ali and Abrar Mohammad Sayaf and Fakhrul Hassan and Usama Ilahi and Mohammed Alissa and Sergio Crovella and Abdullah A. Shaito and Hadi M. Yassine},
journal = {PLOS One},
year = {2026},
month = sep,
doi = {10.1371/journal.pone.0355499},
url = {https://doi.org/10.1371/journal.pone.0355499},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mechanistic inhibition of herpes simplex virus-1 UL21 immune-evasion function by natural-product scaffolds: A multi-tier docking, dynamics, and energetic profiling approach
AU - Muhammad Suleman
AU - Imtiaz Ali
AU - Abrar Mohammad Sayaf
AU - Fakhrul Hassan
AU - Usama Ilahi
AU - Mohammed Alissa
AU - Sergio Crovella
AU - Abdullah A. Shaito
AU - Hadi M. Yassine
PY - 2026
DA - 2026/09/16
JO - PLOS One
DO - 10.1371/journal.pone.0355499
UR - https://doi.org/10.1371/journal.pone.0355499
AB - 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.
SN - 1932-6203
ER -