Virtual Screening on Molecules Targeting the Interaction Between Estrogen Receptor Beta and Murine Double Minute 2

Novyananda Salmasfattah, Nunuk Aries Nurulita, Binar Asrining Dhiani


Estrogen receptor beta (ERβ) is an isoform of estrogen receptor that plays a role in breast cancer. An E3 ubiquitin ligase, murine double minute 2 (MDM2), can bind to ERβ and degrade it. Virtual screening and protein-protein docking studies are one of the approaches that can be performed to discover FDA-approved drugs targeting the interaction of the ERβ-MDM2 complex. This study aimed to conduct virtual screening of 1615 compounds targeting the interaction between ERβ-MDM2 as an initial study to discover potential breast cancer drugs. Biovia Discovery Studio 2021, ClusPro 2.0, PyRx 8.0, and PyMOL software were utilized in this study. ERβ (PDB ID: 3OLS) and MDM2 (PDB ID: 1T4E) receptors were docked to obtain the ERβ-MDM2 protein complex. The ligands used in the virtual screening were FDA-approved drugs downloaded from the ZINC database. PIC and PLIP web tools were also utilized to analyze the amino acid residues involved in the interaction. The virtual screening results showed that ergotamine was the drug with the lowest energy score (-12.0 kcal/mol) among 1057 drugs and was able to establish the strongest interaction between ERβ-MDM2. In conclusion, based on this computational study, ergotamine strengthens the interaction between ERβ-MDM2 and thus could be used as a candidate for breast cancer drug. Thorough validation of in vitro, biochemical, and in vivo studies are needed to confirm this finding.

Keywords: Estrogen receptor beta, breast cancer, protein-protein interaction, MDM2.

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Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., and Jemal, A., 2018, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA. Cancer J. Clin., 68(6), 394-424. CrossRef

Cavasotto, C.N., 2011, Homology models in docking and high-throughput docking, Curr. Top. Med. Chem., 11(12), 1528–1534. CrossRef

Dallakyan, S., and Olson, A.J., 2015, Small-molecule library screening by docking with PyRx, Methods Mol. Biol., 1263. CrossRef

Dhiani, B.A., Nurulita, N.A., and Fitriyani, F., 2022, Protein-protein Docking Studies of Estrogen Receptor Alpha and TRIM56 Interaction for Breast Cancer Drug Screening, Indones. J. Cancer Chemoprevention, 13(1), 46–54. CrossRef

Elebro, K., Borgquist, S., Rosendahl, A.H., Markkula, A., Simonsson, M., Jirström, K., et al., 2017, High Estrogen Receptor β Expression Is Prognostic among Adjuvant Chemotherapy-Treated Patients-Results from a Population-Based Breast Cancer Cohort, Clin. Cancer Res., 23(3), 766–777. CrossRef

Hawse, J.R., Carter, J.M., Aspros, K.G.M., Bruinsma, E.S., Koepplin, J.W., Negron, V., et al., 2020, Optimized immunohistochemical detection of estrogen receptor beta using two validated monoclonal antibodies confirms its expression in normal and malignant breast tissues, Breast Cancer Res. Treat., 179(1), 241–249. CrossRef

Hosford, S.R., and Miller, T.W., 2014, Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways, Pharmgenomics. Pers. Med., 7(1), 203–215. CrossRef

Jena, A.B., and Duttaroy, A.K., 2022, A Computational Approach for Molecular Characterization of Covaxin (BBV152) and Its Ingredients for Assessing Its Efficacy against COVID-19, Futur. Pharmacol, 2(3), 306–319. CrossRef

Kozakov, D., Grove, L.E., Hall, D.R., Bohnuud, T., Mottarella, S.E., Luo, L., et al., 2015, The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins, Nat. Protoc., 10(5), 733-755. CrossRef

Kozakov, D., Hall, D.R., Xia, B., Porter, K.A., Padhorny, D., Yueh, C., et al., 2017, The ClusPro web server for protein–protein docking, Nat. Protoc., 12(2), 255-278. CrossRef

Li, B.H., Ge, J.Q., Wang, Y.L., Wang, L.J., Zhang, Q., and Bian, C., 2021, Ligand-Based and Docking-Based Virtual Screening of MDM2 Inhibitors as Potent Anticancer Agents, Comput. Math. Methods Med., 2021, 3195957. CrossRef

Loibl, S., Poortmans, P., Morrow, M., Denkert, C., and Curigliano, G., 2021, Breast cancer, Lancet, 397(10286), 1750–1769. CrossRef

Marotti, J.D., Collins, L.C., Hu, R., and Tamimi, R.M., 2010, Estrogen receptor-β expression in invasive breast cancer in relation to molecular phenotype: results from the Nurses Health Study, Mod. Pathol., 23(2), 197–204. CrossRef

Mulac, D., and Humpf, H.U., 2011, Cytotoxicity and accumulation of ergot alkaloids in human primary cells, Toxicology, 282(3), 112–121. CrossRef

Mulac, D., Lepski, S., Ebert, F., Schwerdtle, T., and Humpf, H.U., 2013, Cytotoxicity and fluorescence visualization of ergot alkaloids in human cell lines, J. Agric. Food Chem., 61(2), 462–471. CrossRef

Ngo, M., and Tadi, P., 2022, Ergotamine/Caffeine, In StatPearls, StatPearls Publishing. Link

Petta, I., Lievens, S., Libert, C., Tavernier, J., and De Bosscher, K., 2016, Modulation of Protein-Protein Interactions for the Development of Novel Therapeutics, Mol. Ther., 24(4), 707–718. CrossRef

Rajendaran, S., Jothi, A., and Anbazhagan, V., 2020, Targeting the glycan of receptor binding domain with jacalin as a novel approach to develop a treatment against COVID-19, R. Soc. Open Sci., 7, 200844. CrossRef

Razandi, M., Pedram, A., Jordan, V.C., Fuqua, S., and Levin, E.R., 2012, Tamoxifen regulates cell fate through mitochondrial estrogen receptor beta in breast cancer, Oncogene, 32, 3274–3285. CrossRef

Sanchez, M., Picard, N., Sauve, K., and Tremblay, A., 2013, Coordinate regulation of estrogen receptor β degradation by Mdm2 and CREB-binding protein in response to growth signals, Oncogene, 32(1), 117–126. CrossRef

Scabia, V., Ayyanan, A., De Martino, F., Agnoletto, A., Battista, L., Laszlo, C., et al., 2022, Estrogen receptor positive breast cancers have patient specific hormone sensitivities and rely on progesterone receptor, Nat. Commun., 13, 3127. CrossRef

Sterling, T., and Irwin, J.J., 2015, ZINC 15 – Ligand Discovery for Everyone, J. Chem. Inf. Model., 55(11), 2324–2337. CrossRef

Tortorella, P., Laghezza, A., Durante, M., Gomez-Monterrey, I., Bertamino, A., Campiglia, P., et al., 2016, An Effective Virtual Screening Protocol to Identify Promising p53-MDM2 Inhibitors, J. Chem. Inf. Model., 56(6), 1216–1227. CrossRef

Yin, L., Zhang, X.T., Bian, X.W., Guo, Y.M., and Wang, Z.Y., 2014, Disruption of the ER-α36-EGFR/HER2 Positive Regulatory Loops Restores Tamoxifen Sensitivity in Tamoxifen Resistance Breast Cancer Cells, PLoS One, 9(9), e107369. CrossRef

Zheng, Y., Shao, X., Huang, Y., Shi, L., Chen, B., Wang, X., et al., 2016, Role of estrogen receptor in breast cancer cell gene expression, Mol. Med. Rep., 13(5), 4046–4050. CrossRef

Zhou, Y., and Liu, X., 2020, The role of estrogen receptor beta in breast cancer, Biomark. Res., 8(1), 1–12. CrossRef

Zhu, H., Gao, H., Ji, Y., Zhou, Q., Du, Z., Tian, L., et al., 2022, Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials, J. Hematol. Oncol., 15(1), 1–23. CrossRef


Copyright (c) 2022 Novyananda Salmasfattah, Nunuk Aries Nurulita, Binar Asrining Dhiani

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Indonesian Society for Cancer Chemoprevention