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Current Computer-Aided Drug Design


ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Research Article

In silico Molecular Modelling of Selected Natural Ligands and their Binding Features with Estrogen Receptor Alpha

Author(s): V.L. Maruthanila, R. Elancheran*, Nand Kishor Roy, Anupam Bhattacharya, Ajaikumar B. Kunnumakkara, S. Kabilan and Jibon Kotoky

Volume 15 , Issue 1 , 2019

Page: [89 - 96] Pages: 8

DOI: 10.2174/1573409914666181008165356

Price: $65


Background: Breast cancer is one of the most common cancers diagnosed among women. It is now recognized that two receptors mediate estrogen action and the presence of estrogen receptor alpha (ERα) correlates with better prognosis and the likelihood of response to hormonal therapy. ERα is an attractive target for the treatment of breast cancer. Most of the drugs currently used for the breast cancer treatment have numerous side effects and they are often unsuccessful in removing the tumour completely. Hence, we focused on natural compounds like flavonoids, polyphenols, etc. which do not exhibit any high toxic effects against normal cells.

Objectives: To identify the potential natural inhibitors for BCa through an optimised in silico approach.

Methods: Structural modification and molecular docking-based screening approaches were imposed to identify the novel natural compounds by using Schrödinger (Maestro 9.5). The Qikprop v3.5 was used for the evaluation of important ADME parameters and its permissible ranges. Cytotoxicity of the compounds was evaluated by MTT assay against MCF-7 Cell lines.

Results: From the docking studies, we found that the compounds, Myricetin, Quercetin, Apigenin, Luteolin and Baicalein showed the highest Glide Scores -10.78, -9.48, -8.92, -8.87 and -8.82 kcal mol-1 respectively. Of these, Luteolin and Baicalein showed the significant IC50 values (25 ± 4.0 and 58.3 ± 4.4 µM, respectively) against MCF-7 cell line. The ADME profiling of the test compounds was evaluated to find the drug-likeness and pharmacokinetic parameters.

Conclusion: We mainly focused on in silico study to dock the compounds into the human estrogen receptor ligand binding domain (hERLBD) and compare their predicted binding affinity with known antiestrogens. Myricetin, Quercetin, Apigenin, Luteolin and Baicalein were identified as the most promising among all. Of these, Luteolin and Baicalein showed significant anticancer activities against MCF-7 cell line. These findings may provide basic information for the development of anti-breast cancer agents.

Keywords: Estrogen receptor alpha, breast cancer, molecular docking, natural compounds, schrödinger, Quercetin.

Graphical Abstract
Elancheran, R.; Maruthanila, V.L.; Ramanathan, M.; Kabilan, S.; Devi, R.; Kunnumakara, A.; Kotoky, J. Recent discoveries and developments of androgen receptor based therapy for prostate cancer. MedChemComm, 2015, 6(5), 746-768.
Howlader, N.; Noone, A.M. Krapcho. M.; Miller, D.; Bishop, K.; Altekruse, S.F.; Kosary, C.L.; Yu, M.; Ruhl, J.; Tatalovich, Z.; Mariotto, A.; Lewis, D.R.; Chen, H.S.; Feuer, E.J.; Cronin, K.A. (eds) SEER Cancer Statistics Review, 1975-2013. National Cancer Institute. Bethesda MD, based on November 2015 SEER data submission, posted to the SEER web site, April 2016
Kumar, R.; Zakharov, M.N.; Khan, S.H.; Miki, R.; Jang, H.; Toraldo, G.; Singh, R.; Bhasin, S.; Jasuja, R. The dynamic structure of the estrogen receptor. J. Amino Acids, 2011.
Dhananjaya, K.; Sibi, G.; Mallesha, H.; Ravikumar, K.R.; Awasthi, S. Insilico studies of daidzein and genistein with human estrogen receptor α. Asian Pacific. J. Trop. Biomed., 2012, 2(3), S1747-S1753.
Motaghed, M.; Al-Hassan, F.M.; Hamid, S.S. Cellular responses with thymoquinone treatment in human breast cancer cell line MCF-7. Pharmaco.Res, 2013, 5(3), 200-206.
Maruthanila, V.L.; Elancheran, R.; Kunnumakkara, A.B.; Kabilan, S.; Kotoky, J. Recent development of targeted approaches for the treatment of breast cancer. Breast Cancer, 2017, 24(2), 191-219.
Noori, S.; Hassan, Z.M. Tehranolide inhibits proliferation of MCF-7 human breast cancer cells by inducing G0/G1 arrest and apoptosis. Free Radic. Biol. Med., 2012, 52(9), 1987-1999.
Boger, D.L.; Patane, M.A.; Jin, Q.; Kitos, P.A. Design, synthesis and evaluation of bouvardin, deoxybouvardin and RA-I-XIV pharmacophore analogs. Bioorg. Med. Chem., 1994, 2(2), 85-100.
Lin, R.; Kim, H.; Hong, J.; Li, Q.J. Biological Evaluation of Subglutinol A as a novel immunosuppressive agent for inflammation intervention. ACS Med. Chem. Lett., 2014, 5(5), 485-490.
Maruthanila, V.L.; Poornima, J.; Mirunalini, S. Attenuation of carcinogenesis and the mechanism underlying by the influence of indole-3-carbinol and its metabolite 3, 3′-diindolylmethane: A therapeutic marvel. Adv. Pharmacol. Sci., 2014.
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(7), 927-937.
Schrödinger, LLC New York, NY. Glide, version 6.1. 2013
Schrödinger, L.L.C. Qikprop, version 3.5, New York, NY. 2010
Elancheran, R.; Saravanan, K.; Choudhury, B.; Divakar, S.; Kabilan, S.; Ramanathan, M.; Das, B.; Devi, R.; Kotoky, J. Design and development of oxobenzimidazoles as novel androgen receptor antagonists. Med. Chem. Res., 2016, 25(4), 539-552.
Kumar, D.; Khare, G.; Kidwai, S.; Tyagi, A.K.; Singh, R.; Rawat, D.S. Novel isoniazid–amidoether derivatives: Synthesis, characterization and antimycobacterial activity evaluation. MedChemComm, 2015, 6(1), 131-137.
Itteboina, R.; Ballu, S.; Sivan, S.K.; Manga, V. Molecular docking, 3D QSAR and dynamics simulation studies of imidazo-pyrrolopyridines as janus kinase 1 (JAK 1) inhibitors. Comput. Biol. Chem., 2016, 64, 33-46.
Saravanan, K.; Elancheran, R.; Divakar, S.; Anand, S.A.A.; Ramanathan, M.; Kotoky, J.; Lokanath, N.K.; Kabilan, S. Design, synthesis and biological evaluation of 2-(4-phenylthiazol-2-yl) isoindoline-1, 3-dione derivatives as anti-prostate cancer agents. Bioorg. Med. Chem. Lett., 2017, 27(5), 1199-1204.
Elancheran, R.; Saravanan, K.; Divakar, S.; Kumari, S.; Maruthanila, V.L.; Kabilan, S.; Ramanathan, M.; Devi, R.; Kotoky, J. Design, synthesis and biological evaluation of novel 1, 3-thiazolidine-2, 4-diones as anti-prostate cancer agents. Anticancer. Agents Med. Chem., 2017.
Divakar, S.; Saravanan, K.; Karthikeyan, P.; Elancheran, R.; Kabilan, S.; Balasubramanian, K.K.; Devi, R.; Kotoky, J.; Ramanathan, M. Iminoenamine based novel androgen receptor antagonist exhibited anti-prostate cancer activity in androgen independent prostate cancer cells through inhibition of AKT pathway. Chemico-Biological. Interact., 2017, 275, 22-34.

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