Volume 6 Number 2 2022
Computational Exploration of Xanthohumol as a Safer Natural Substitute for Tamoxifen in Estrogen Receptor-Positive Breast Cancer
Amena Khatun Manica1*, Most Farhana Akter2, Md. Robiul Islam2, Tufael3, Md Abu Bakar Siddique4
Journal of Angiotherapy 6 (2) 1-9 https://doi.org/10.25163/angiotherapy.6210431
Submitted: 04 January 2022 Revised: 17 March 2022 Accepted: 24 March 2022 Published: 26 March 2022
Abstract
Background: Breast cancer remains a major health burden, with estrogen receptor-positive (ER?) subtypes constituting most cases. Tamoxifen, a selective estrogen receptor modulator (SERM), has been a frontline therapy for decades, yet its long-term use often leads to toxicity, resistance, and pharmacokinetic limitations. This study employed in-silico approaches to assess xanthohumol, a prenylated chalcone derived from Humulus lupulus, as a potential natural substitute for tamoxifen.
Method: Using AutoDock Vina (PDB: 3ERT), both ligands were docked to the ERα ligand-binding domain.
Results: Xanthohumol displayed a slightly superior binding affinity (−8.0 kcal/mol) compared to tamoxifen (−7.5 kcal/mol) and formed a stabilizing hydrogen bond with MET522, along with π–π interactions with TRP383, unlike tamoxifen’s purely hydrophobic contacts. SwissADME analysis revealed xanthohumol to possess better solubility, high gastrointestinal absorption, and no Lipinski violations, indicating strong drug-likeness. ProTox-II toxicity predictions demonstrated a higher LD50 (3800 mg/kg) and fewer toxic liabilities for xanthohumol, while tamoxifen showed elevated neurotoxicity and CYP3A4 interaction risks. The BOILED-Egg model further indicated that xanthohumol has high intestinal absorption but limited blood–brain barrier permeability, suggesting reduced neurotoxic potential.
Conclusion: Overall, these computational findings support xanthohumol as a pharmacologically favorable and safer natural alternative to tamoxifen. Further in-vitro and in-vivo validation is warranted to substantiate its therapeutic viability in hormone-dependent breast cancer.
Keywords: Xanthohumol; Tamoxifen; Estrogen Receptor Alpha (ERα); Molecular Docking; ADMET Analysis
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