{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Biomedical Research Center (BRC), QU Health, Qatar University, Doha, Qatar",
    "Center for Biotechnology and Microbiology, University of Swat, Swat, Pakistan",
    "School of Chemical Sciences, Universiti Sains Malaysia, Gelugor, Penang, Malaysia",
    "Department of Medical Laboratory Technology, Faculty of Rehabilitation and Allied Health Sciences, Riphah International University, Islamabad, Pakistan",
    "Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia",
    "Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Muhammad Suleman"
    },
    {
      "affs": [
        1
      ],
      "name": "Imtiaz Ali"
    },
    {
      "affs": [
        2
      ],
      "name": "Abrar Mohammad Sayaf"
    },
    {
      "affs": [
        3
      ],
      "name": "Fakhrul Hassan"
    },
    {
      "affs": [
        4
      ],
      "name": "Usama Ilahi"
    },
    {
      "affs": [
        5
      ],
      "name": "Mohammed Alissa"
    },
    {
      "name": "Sergio Crovella"
    },
    {
      "name": "Abdullah A. Shaito"
    },
    {
      "name": "Hadi M. Yassine"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bmafqse9rk4ce.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pone.0355499",
  "fulltext_url": null,
  "id": "bmafqse9rk4ce",
  "issns": [
    "1932-6203"
  ],
  "landing_url": "https://doi.org/10.1371/journal.pone.0355499",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1703|Computational Drug Discovery Methods"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Biochemical simulations"
    ],
    [
      "plos",
      "/Biology and life sciences/Computational biology/Biochemical simulations"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Herpesviruses/Herpes simplex virus/Herpes simplex virus-1"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Viruses/DNA viruses/Herpesviruses/Herpes simplex virus/Herpes simplex virus-1"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Herpesviruses/Herpes simplex virus/Herpes simplex virus-1"
    ],
    [
      "plos",
      "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Herpesviruses/Herpes simplex virus/Herpes simplex virus-1"
    ],
    [
      "plos",
      "/Medicine and health sciences/Pharmacology/Drug interactions"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Computational chemistry/Molecular dynamics"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Physical chemistry/Chemical bonding/Hydrogen bonding"
    ],
    [
      "plos",
      "/Physical sciences/Mathematics/Statistics/Statistical methods/Multivariate analysis/Principal component analysis"
    ],
    [
      "plos",
      "/Physical sciences/Physics/Thermodynamics/Free energy"
    ],
    [
      "plos",
      "/Research and analysis methods/Chemical characterization/Binding analysis"
    ],
    [
      "plos",
      "/Research and analysis methods/Mathematical and statistical techniques/Statistical methods/Multivariate analysis/Principal component analysis"
    ]
  ],
  "openalex": "W7213399438",
  "pdf_url": "https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0355499&type=printable",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-16",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/bmafqse9rk4ce.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:49Z",
      "native_id": "10.1371/journal.pone.0355499",
      "source": "plos",
      "url": "https://doi.org/10.1371/journal.pone.0355499"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "plos:computational biology",
      "subfield": "bioinformatics"
    },
    {
      "field": "biology",
      "origin": "plos:microbiology",
      "subfield": "microbiology"
    },
    {
      "field": "mathematics",
      "origin": "plos:statistical methods",
      "subfield": "statistics"
    }
  ],
  "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",
  "title_text": "Mechanistic inhibition of herpes simplex virus-1 UL21 immune-evasion function by natural-product scaffolds: A multi-tier docking, dynamics, and energetic profiling approach",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:49Z",
  "url": "https://research.draconitic.com/paper/bmafqse9rk4ce",
  "venue": "PLOS One",
  "versions": []
}