{
  "abstract": "Prenylation of phenolic and aromatic natural products across plants, bacteria, and higher organisms contributes to their lipophilicity and biological function. The process also enhances host defense and serves as a building block for chemical diversity, with medicinal chemistry mimicking these effects to create more effective compounds. While phytoestrogens, particularly those from licorice, are established as key natural regulators of estrogen receptor (ER) biology, the specific mechanisms by which prenylated polyphenolics in licorice regulate ER ligand binding and activity remain unknown. Herein, we show that the widespread prenylation of stilbenes from two commonly used licorice species reveals a broad spectrum of ER interaction profiles in the context of different scaffolds. To identify structural rules for how prenylation modulates ligand binding, we synthesized 16 mono- or diprenylated stilbennoid analogs based on common resveratrol or dihydroresveratrol cores. These variously prenylated stilbenoid compounds exhibited ER agonistic effects on cell growth with a remarkable 5-log range of cellular potencies. X-ray crystal structures of these compounds with ERα showed that this wide range of activities were found in essentially identical ligand–receptor structural states, except for differing side chain rotamers in one region of the binding pocket that accommodates the prenyl substituents. Thus, chemical diversity from a simple class of stilbenoids generated biological diversity through the modular combination of prenyl substitutions that revealed localized structural flexibility in an otherwise highly stable ER agonist conformation. The emergence of this prenylation code provides guidance for understanding and predicting the effect of prenyl-like substitution on phytoestrogens and other ER ligands.",
  "abstract_shown": true,
  "affiliations": [
    "National Center for Natural Products Research, School of Pharmacy, University of Mississippi , University, MS 38677 ,",
    "Faculty of Pharmacy, Philadelphia University , Amman 19392 ,",
    "Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi , University, MS 38677 ,",
    "Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , Jupiter, FL 33458 ,",
    "Department of Chemistry, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , Jupiter, FL 33458 ,",
    "Department of Chemistry, University of Illinois , Urbana, IL 61801 ,"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Manal Alhusban"
    },
    {
      "affs": [
        0
      ],
      "name": "Saqlain Haider",
      "orcid": "0000-0002-1738-6945"
    },
    {
      "affs": [
        0
      ],
      "name": "Pankaj Pandey",
      "orcid": "0000-0001-9128-8254"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Abidah Parveen",
      "orcid": "0000-0003-4157-8864"
    },
    {
      "affs": [
        3
      ],
      "name": "Ashley T Arbesfeld",
      "orcid": "0009-0003-0470-2149"
    },
    {
      "affs": [
        3
      ],
      "name": "Jerome C Nwachukwu",
      "orcid": "0000-0003-4313-9187"
    },
    {
      "affs": [
        4
      ],
      "name": "Tina Izard",
      "orcid": "0000-0002-2895-483X"
    },
    {
      "affs": [
        3
      ],
      "name": "Kendall W Nettles",
      "orcid": "0000-0003-2917-7574"
    },
    {
      "affs": [
        5
      ],
      "name": "John A Katzenellenbogen",
      "orcid": "0000-0003-0914-0010"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Ikhlas A Khan",
      "orcid": "0000-0001-5464-4643"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Amar G Chittiboyina",
      "orcid": "0000-0002-7047-5373"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3qs997ew3268s.bib",
  "cited_by": 0,
  "doi": "10.1093/pnasnexus/pgag351",
  "fulltext_url": "https://europepmc.org/articles/PMC13712132",
  "id": "3qs997ew3268s",
  "issns": [
    "2752-6542"
  ],
  "landing_url": "https://academic.oup.com/pnasnexus/article/doi/10.1093/pnasnexus/pgag351/8892677",
  "language": "eng",
  "licence": "CC-BY-NC-4.0",
  "licence_label": "CC BY-NC 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "AcademicSubjects/MED00010"
    ],
    [
      "heading",
      "AcademicSubjects/SCI00010"
    ],
    [
      "heading",
      "AcademicSubjects/SOC00010"
    ],
    [
      "heading",
      "Biological, Health, and Medical Sciences"
    ],
    [
      "heading",
      "PNAS_Nexus/pharm"
    ],
    [
      "heading",
      "Pharmacology"
    ],
    [
      "openalex",
      "1311|Estrogen and related hormone effects"
    ]
  ],
  "openalex": "W7221164492",
  "pdf_url": "https://academic.oup.com/pnasnexus/advance-article-pdf/doi/10.1093/pnasnexus/pgag351/71753488/pgag351.pdf",
  "pmcid": "PMC13712132",
  "pmid": "42948300",
  "published": "2026-10-09",
  "publisher": "Oxford University Press (OUP)",
  "ris": "https://research.draconitic.com/paper/3qs997ew3268s.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:43Z",
      "native_id": "10.1093/pnasnexus/pgag351",
      "source": "crossref",
      "url": "https://academic.oup.com/pnasnexus/article/doi/10.1093/pnasnexus/pgag351/8892677"
    },
    {
      "first_seen": "2026-10-31T00:20:34Z",
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      "url": "https://europepmc.org/article/MED/42948300"
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    {
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      "native_id": "PMC13712132",
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      "url": "https://doi.org/10.1093/pnasnexus/pgag351"
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  "subjects": [
    {
      "field": "medicine",
      "origin": "heading:Pharmacology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "The prenylation code regulating estrogenic activity of synthetic and natural product derivatives of resveratrol",
  "title_text": "The prenylation code regulating estrogenic activity of synthetic and natural product derivatives of resveratrol",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:22:46Z",
  "url": "https://research.draconitic.com/paper/3qs997ew3268s",
  "venue": "PNAS Nexus",
  "versions": []
}