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PreprintCC BY-NCChemRxiv

Bioisosteric Design of Novel Flavonoid-Derived Aromatase Inhibitors to Reduce Estradiol Biosynthesis in ER+ Breast Cancer

  • Zion Beason1,2,3
  • Arslan Sheikh4,5
5 affiliations
  1. 1Department of Career and Technical Education
  2. 2Iowa Colony High School
  3. 3Alvin College
  4. 4Center for Drug Discovery
  5. 5Northeastern University
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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.

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Cite

BibTeXRIS
BibTeX
@misc{beason2026bioisosteric,
  title = {{Bioisosteric Design of Novel Flavonoid-Derived Aromatase Inhibitors to Reduce Estradiol Biosynthesis in ER+ Breast Cancer}},
  author = {Zion Beason and Arslan Sheikh},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15008946/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008946/v1},
  note = {CC BY-NC},
}
RIS
TY  - UNPB
TI  - Bioisosteric Design of Novel Flavonoid-Derived Aromatase Inhibitors to Reduce Estradiol Biosynthesis in ER+ Breast Cancer
AU  - Zion Beason
AU  - Arslan Sheikh
PY  - 2026
DA  - 2026/09/16
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15008946/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008946/v1
AB  - 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.
ER  -