Vol 68 No 3 (2023): Journal of the Chilean Chemical Society
Original Research Papers


Dayana Alonso
Laboratory of Synthetic and Biomolecular Chemistry, Faculty of Chemistry, University of Havana, Zapata and G, Havana 10400, Cuba.
Dayana Mesa
Center for Natural Product Research, Faculty of Chemistry, University of Havana, Zapata and G, Havana 10400, Cuba.
Giselle Hernández
Center for Natural Product Research, Faculty of Chemistry, University of Havana, Zapata and G, Havana 10400, Cuba.
Andres F. Olea
Grupo QBAB, Instituto de Ciencias Aplicadas, Facultad de Ingeniería, Universidad Autónoma de Chile, Llano Subercaseaux 2801, San Miguel, Santiago, Chile.
Luis Espinoza
Departamento de Química, Universidad Técnica Federico Santa María, Avenida España 1680, Valparaíso 2340000, Chile
Yamilet Coll
Center for Natural Product Research, Faculty of Chemistry, University of Havana, Zapata and G, Havana 10400, Cuba.
Published December 31, 2023
  • breast cancer,
  • estrogen receptor,
  • docking,
  • hydroxyimino steroid
How to Cite
Alonso, D., Mesa, D., Hernández, G., Olea, A. F., Espinoza, L., & Coll, Y. (2023). DOCKING SIMULATIONS OF STEROIDAL OXIMES TOWARD ESTROGEN RECEPTOR ALPHA. ANALYSIS OF THEIR POTENTIAL ANTICANCER ACTIVITY. Journal of the Chilean Chemical Society, 68(3), 5918-5923. Retrieved from


Breast cancer is the most common cause of cancer deaths in women. Normal breast cells and most breast cancer cells have receptors that attach to circulating estrogen and progesterone. Estrogen and progesterone bind to the receptors and may cause cancer cells to proliferate. Drugs, currently being used to treat this disease are not so effective and cause adverse effects. For this reason, the quest of new compounds that bind to the estrogen receptor (ER), activating or inhibiting ERs selectively, is a very active field of research. In this task, molecular docking plays a vital role in drug design, either as a tool in drug discovery and analysis of protein-ligand interactions. In this work, 26 steroidal oximes, which are derivatives of diosgenin, were analyzed using docking studies, and compared against the estrogen receptor (ERa). The 3D structures of ERa were downloaded from Protein Data Bank (3ERT) and optimized using Modifications in rings A and B were made, and both oxime configurations (E or Z) were considered. Results for hydroximino steroids were compared with those obtained for compounds exhibiting biological activity against this type of cancer, namely, 4-hydroxytamoxifen, diosgenin and 6,23-dihydroximino diosgenin derivative. Molecular docking studies on ERa revealed that three mono oximes were found to interact with the protein more efficiently and have the best docking score. Thus, modification of diosgenin with oxime groups could lead to antiproliferative steroidal compounds, and therefore they could be considered for further research and in vivo evaluations for breast cancer treatment and management strategies


  2. Yue, W.; Fan, P.; Wang, J.; Li, Y.; Santen, R. J., Mechanisms of acquired resistance to endocrine therapy in hormone-dependent breast cancer cells. J. Steroid Biochem. Mol. Biol. 2007, 106, 102-110.
  3. Ulm, M.; Ramesh, A. V.; McNamara, K. M.; Ponnusamy, S.; Sasano, H.; Narayanan, R., Therapeutic advances in hormone-dependent cancers: focus on prostate, breast and ovarian cancers. Endocr Connect 2019, 8, R10-R26.
  4. Lee, H.-R.; Kim, T.-H.; Choi, K.-C., Functions and physiological roles of two types of estrogen receptors, ERα and ERβ, identified by estrogen receptor knockout mouse. Lab Anim Res 2012, 28, 71-76.
  5. Paterni, I.; Granchi, C.; Katzenellenbogen, J. A.; Minutolo, F., Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potential. Steroids 2014, 90, 13-29.
  6. Santen, R. J.; Manni, A.; Harvey, H.; Redmond, C., Endocrine Treatment of Breast Cancer in Women. Endocrine Reviews 1990, 11, 221-265.
  7. Lumachi, F.; Luisetto, G.; Basso, S. M.; Basso, U.; Brunello, A.; Camozzi, V., Endocrine therapy of breast cancer. Curr Med Chem 2011, 18, 513-22.
  8. Łukasiewicz, S.; Czeczelewski, M.; Forma, A.; Baj, J.; Sitarz, R.; Stanisławek, A., Breast Cancer-Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies-An Updated Review. Cancers (Basel) 2021, 13, 4287.
  9. Shiau, A. K.; Barstad, D.; Loria, P. M.; Cheng, L.; Kushner, P. J.; Agard, D. A.; Greene, G. L., The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998, 95, 927-37.
  10. Martinkovich, S.; Shah, D.; Planey, S. L.; Arnott, J. A., Selective estrogen receptor modulators: tissue specificity and clinical utility. Clin Interv Aging 2014, 9, 1437-52.
  11. Sharma, D.; Kumar, S.; Narasimhan, B., Estrogen alpha receptor antagonists for the treatment of breast cancer: a review. Chem Cent J 2018, 12, 107-107.
  12. Wang, L.; Sharma, A., The Quest for Orally Available Selective Estrogen Receptor Degraders (SERDs). ChemMedChem 2020, 15, 2072-2097.
  13. Ponder, J. W.; Case, D. A., Force Fields for Protein Simulations. In Advances in Protein Chemistry, Academic Press: 2003; Vol. 66, pp 27-85.
  14. Leese, M. P.; Leblond, B.; Newman, S. P.; Purohit, A.; Reed, M. J.; Potter, B. V. L., Anti-cancer activities of novel D-ring modified 2-substituted estrogen-3-O-sulfamates. J. Steroid Biochem. Mol. Biol. 2005, 94, 239-251.
  15. Allan, G. M.; Lawrence, H. R.; Cornet, J.; Bubert, C.; Fischer, D. S.; Vicker, N.; Smith, A.; Tutill, H. J.; Purohit, A.; Day, J. M.; Mahon, M. F.; Reed, M. J.; Potter, B. V. L., Modification of Estrone at the 6, 16, and 17 Positions: Novel Potent Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1. J. Med. Chem. 2006, 49, 1325-1345.
  16. Boström, J.; Hogner, A.; Schmitt, S., Do Structurally Similar Ligands Bind in a Similar Fashion? J. Med. Chem. 2006, 49, 6716-6725.
  17. Alsayari, A.; Kopel, L.; Ahmed, M. S.; Pay, A.; Carlson, T.; Halaweish, F. T., Design, synthesis, and biological evaluation of steroidal analogs as estrogenic/anti-estrogenic agents. Steroids 2017, 118, 32-40.
  18. Canário, C.; Matias, M.; Brito, V.; Santos, A. O.; Falcão, A.; Silvestre, S.; Alves, G., New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies. Molecules 2021, 26.
  19. Jindal, D. P.; Chattopadhaya, R.; Guleria, S.; Gupta, R., Synthesis and antineoplastic activity of 2-alkylaminoethyl derivatives of various steroidal oximes. European Journal of Medicinal Chemistry 2003, 38, 1025-1034.
  20. Iqbal Choudhary, M.; Shahab Alam, M.; Atta ur, R.; Yousuf, S.; Wu, Y.-C.; Lin, A.-S.; Shaheen, F., Pregnenolone derivatives as potential anticancer agents. Steroids 2011, 76, 1554-1559.
  21. Martínez-Pascual, R.; Meza-Reyes, S.; Vega-Baez, J. L.; Merino-Montiel, P.; Padrón, J. M.; Mendoza, Á.; Montiel-Smith, S., Novel synthesis of steroidal oximes and lactams and their biological evaluation as antiproliferative agents. Steroids 2017, 122, 24-33.
  22. Wendlandt, A. E.; Yelton, S. M.; Lou, D.; Watt, D. S.; Noonan, D. J., Synthesis and functional analysis of novel bivalent estrogens. Steroids 2010, 75, 825-833.
  23. He, Z.; Chen, H.; Li, G.; Zhu, H.; Gao, Y.; Zhang, L.; Sun, J., Diosgenin inhibits the migration of human breast cancer MDA-MB-231 cells by suppressing Vav2 activity. Phytomedicine 2014, 21, 871-6.
  24. Sethi, G.; Shanmugam, M. K.; Warrier, S.; Merarchi, M.; Arfuso, F.; Kumar, A. P.; Bishayee, A., Pro-Apoptotic and Anti-Cancer Properties of Diosgenin: A Comprehensive and Critical Review. Nutrients 2018, 10.
  25. Sánchez-Sánchez, L.; Hernández-Linares, M. G.; Escobar, M. L.; López-Muñoz, H.; Zenteno, E.; Fernández-Herrera, M. A.; Guerrero-Luna, G.; Carrasco-Carballo, A.; Sandoval-Ramírez, J., Antiproliferative, Cytotoxic, and Apoptotic Activity of Steroidal Oximes in Cervicouterine Cell Lines. Molecules 2016, 21, 1533.
  26. Masood Ur, R.; Mohammad, Y.; Fazili, K. M.; Bhat, K. A.; Ara, T., Synthesis and biological evaluation of novel 3-O-tethered triazoles of diosgenin as potent antiproliferative agents. Steroids 2017, 118, 1-8.
  27. Zhang, J.; Wang, X.; Yang, J.; Guo, L.; Wang, X.; Song, B.; Dong, W.; Wang, W., Novel diosgenin derivatives containing 1,3,4-oxadiazole/thiadiazole moieties as potential antitumor agents: Design, synthesis and cytotoxic evaluation. Eur J Med Chem 2020, 186, 111897.
  28. Waterhouse, A.; Bertoni, M.; Bienert, S.; Studer, G.; Tauriello, G.; Gumienny, R.; Heer, F. T.; de Beer, T. A. P.; Rempfer, C.; Bordoli, L.; Lepore, R.; Schwede, T., SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res 2018, 46, W296-w303.
  29. Dolinsky, T. J.; Nielsen, J. E.; McCammon, J. A.; Baker, N. A., PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations. Nucleic Acids Res 2004, 32, W665-7.
  30. Hanwell, M. D.; Curtis, D. E.; Lonie, D. C.; Vandermeersch, T.; Zurek, E.; Hutchison, G. R., Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. Journal of Cheminformatics 2012, 4, 17.
  31. Halgren, T. A., Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J. Comput. Chem. 1996, 17, 490-519.
  32. Stewart, J. J. P. MOPAC2016, Stewart Computational Chemistry.
  33. Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R. K.; Goodsell, D. S.; Olson, A. J., AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009, 30, 2785-91.
  34. Trott, O.; Olson, A. J., AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 2010, 31, 455-461.
  35. Durrant, J. D.; McCammon, J. A., BINANA: a novel algorithm for ligand-binding characterization. J Mol Graph Model 2011, 29, 888-893.
  36. Mantsyzov, A. B.; Bouvier, G.; Evrard-Todeschi, N.; Bertho, G., Contact-based ligand-clustering approach for the identification of active compounds in virtual screening. Adv Appl Bioinform Chem 2012, 5, 61-79.
  37. Rosenfeld, R. J.; Goodsell, D. S.; Musah, R. A.; Morris, G. M.; Goodin, D. B.; Olson, A. J., Automated docking of ligands to an artificial active site: augmenting crystallographic analysis with computer modeling. Journal of Computer-Aided Molecular Design 2003, 17, 525-536.
  38. Deng, Z.; Chuaqui, C.; Singh, J., Structural Interaction Fingerprint (SIFt): A Novel Method for Analyzing Three-Dimensional Protein−Ligand Binding Interactions. J. Med. Chem. 2004, 47, 337-344.
  39. Renner, S.; Derksen, S.; Radestock, S.; Mörchen, F., Maximum Common Binding Modes (MCBM): Consensus Docking Scoring Using Multiple Ligand Information and Interaction Fingerprints. J. Chem. Inf. Model. 2008, 48, 319-332.
  40. Payton-Stewart, F.; Tilghman, S. L.; Williams, L. G.; Winfield, L. L., Benzimidazoles diminish ERE transcriptional activity and cell growth in breast cancer cells. Biochemical and Biophysical Research Communications 2014, 450, 1358-1362.
  41. Martinez, R. Nuevas metodologías para la síntesis de azaesteroides. Universidad Autónoma de Puebla, Puebla, Mexico, 2017.
  42. Zafar, A.; Ahmad, S.; Naseem, I., Insight into the structural stability of coumestrol with human estrogen receptor α and β subtypes: a combined approach involving docking and molecular dynamics simulation studies. RSC Advances 2015, 5, 81295-81312.

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