{
  "abstract": "Estrogen receptor-positive (ER+) breast cancer is a hormonal cancer in which tumor proliferation is dependent on estrogen via androgen-to-estrogen conversion, facilitated by the aromatase enzyme (CYP19A1). Aromatase inhibitors (AIs) are often first-line treatments for ER+ breast cancer, yet the three FDA-approved agents present potentially mitigable pharmacological issues and distinct side-effect profiles. To expand structural diversity and improve pharmacological properties, a computational hit-to-lead pipeline was executed. A virtual hit screen of ten selected natural flavonoids against human aromatase (PDB ID: 3S79) across 100 dockings revealed Chrysin consistently outperformed other flavonoid ligands on all measured thermodynamic metrics, with 51% of poses scoring an energy (ΔG) ≤ -5.9 kcal/mol. Using target-based and bioisosteric substitution, a lead series of Chrysin-based analogs called Arcflavonoids (ARC) was engineered in PyMOL. SwissADME predicted the optimized ARC series was leadlike and features reduced cross-inhibition of the major drug-processing CYP450 enzymes, relative to existing commercial AIs. Utilizing comparative molecular docking against both historic and current-generation AIs, we observed that all leads demonstrated steroidal cleft coordination and no heme-iron interaction. Through steroidal cleft interaction, a top lead, ARC48, achieved a predicted ΔG < -10.00 kcal/mol and an inhibition constant (Ki) of 10.34 nM. This optimized, non-steroidal series offers a promising strategy to mitigate adverse reactions from historical AIs.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Career and Technical Education",
    "Iowa Colony High School",
    "Alvin College",
    "Center for Drug Discovery",
    "Northeastern University"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Zion Beason",
      "orcid": "0009-0004-9072-7015"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Arslan Sheikh"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/01tb026j9y431.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15008946/v1",
  "fulltext_url": null,
  "id": "01tb026j9y431",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008946/v1",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1703|Computational Drug Discovery Methods"
    ]
  ],
  "openalex": "W7213445580",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15008946/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-16",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/01tb026j9y431.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:19Z",
      "native_id": "10.26434/chemrxiv.15008946",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008946/v1"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "source:chemrxiv",
      "subfield": "general"
    }
  ],
  "title": "Bioisosteric Design of Novel Flavonoid-Derived Aromatase Inhibitors to Reduce Estradiol Biosynthesis in ER+ Breast Cancer",
  "title_text": "Bioisosteric Design of Novel Flavonoid-Derived Aromatase Inhibitors to Reduce Estradiol Biosynthesis in ER+ Breast Cancer",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:19Z",
  "url": "https://research.draconitic.com/paper/01tb026j9y431",
  "venue": "ChemRxiv",
  "versions": []
}