Bioisosteric Design of Novel Flavonoid-Derived Aromatase Inhibitors to Reduce Estradiol Biosynthesis in ER+ Breast Cancer
Year: 2026
Type: preprint
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.
Source: ChemRxiv
Authors: Zion Beason, Arslan Sheikh
Institution: Northeastern University
Language: English
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7213445580