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<p>Breast cancer is a leading cause of cancer death in women, driven largely by estrogen receptor alpha (ERα), with tamoxifen serving as the standard life-saving treatment for this subtype. Here, we report the molecular docking evaluation of some new 2<i>H</i>-furo[3,2-c]chromene-2,4(3<i>H</i>)-dione derivatives (<b>A-G</b>) against four estrogen receptor targets (1M2P, 1M2R, 2OXX, 2YLY), using tamoxifen and its active metabolite 4‑hydroxytamoxifen (4‑OHT) as reference comparators. The results consistently identified 3-((4-nitrophenyl)amino)-4<i>H</i>-furo[3,2-c]chromene-2,4(3<i>H</i>)-dione derivative (<b>F</b>) as the most promising ligand, exhibiting superior binding affinity and a more favorable interaction profile across all protein conformations compared to tamoxifen. While the active metabolite 4-OHT showed stronger binding affinities to ERα (-11.6, -11.2 and − 11.4&#xa0;kcal/mol) than compound <b>F</b> (-10.3, -9.9 and − 9.3&#xa0;kcal/mol), compound <b>F</b> exhibited more consistent binding across both ERα and ERβ subtypes. Notably, 4‑OHT showed weaker binding to ER<i>β</i> (-6.6&#xa0;kcal/mol) compared to compound <b>F</b> (-7.3&#xa0;kcal/mol). The integrated ADME analysis reveals that unlike 4‑OHT, which exhibits extensive CYP inhibition (CYP2C19, CYP2D6, CYP3A4) and P‑gp interactions, compound <b>F</b> presents a cleaner pharmacokinetic profile with selective CYP1A2 inhibition and no P‑gp modulation, suggesting a lower risk of drug-drug interactions. Therefore, compound <b>F</b> is established as the lead candidate in this study, providing a strong foundation for the design and development of novel anticancer agents with a balanced profile of efficacy and safety.</p>

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Computational evaluation of furo[3,2-c]chromenes as anti-breast cancer agents targeting estrogen receptors: molecular docking, ADME prediction and comparison with tamoxifen and 4-hydroxytamoxifen

  • 期刊论文

  • 发表日期：

    2026年7月11日

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  • Monir Shalbafan,
  • Abolfazl Olyaei,
  • Mahdieh Sadeghpour,
  • Seyede Bita Sajjadi

摘要

Breast cancer is a leading cause of cancer death in women, driven largely by estrogen receptor alpha (ERα), with tamoxifen serving as the standard life-saving treatment for this subtype. Here, we report the molecular docking evaluation of some new 2H-furo[3,2-c]chromene-2,4(3H)-dione derivatives (A-G) against four estrogen receptor targets (1M2P, 1M2R, 2OXX, 2YLY), using tamoxifen and its active metabolite 4‑hydroxytamoxifen (4‑OHT) as reference comparators. The results consistently identified 3-((4-nitrophenyl)amino)-4H-furo[3,2-c]chromene-2,4(3H)-dione derivative (F) as the most promising ligand, exhibiting superior binding affinity and a more favorable interaction profile across all protein conformations compared to tamoxifen. While the active metabolite 4-OHT showed stronger binding affinities to ERα (-11.6, -11.2 and − 11.4 kcal/mol) than compound F (-10.3, -9.9 and − 9.3 kcal/mol), compound F exhibited more consistent binding across both ERα and ERβ subtypes. Notably, 4‑OHT showed weaker binding to ERβ (-6.6 kcal/mol) compared to compound F (-7.3 kcal/mol). The integrated ADME analysis reveals that unlike 4‑OHT, which exhibits extensive CYP inhibition (CYP2C19, CYP2D6, CYP3A4) and P‑gp interactions, compound F presents a cleaner pharmacokinetic profile with selective CYP1A2 inhibition and no P‑gp modulation, suggesting a lower risk of drug-drug interactions. Therefore, compound F is established as the lead candidate in this study, providing a strong foundation for the design and development of novel anticancer agents with a balanced profile of efficacy and safety.