Open Access
Subscription or Fee Access
Computational Molecular Docking Studies to Design Novel 2, 3-Substituted-1-(4-(Piperidin-1-yl) butyl)-1H-indol-5-ol Derivatives for Estrogen Receptor Alfa in AF-2 Domain
Abstract
The present manuscript describes the designing of novel 2, 3-Substituted-1-(4-(Piperidin-1-yl) butyl)-1H-indol-5-ol derivatives as specific estrogen receptor alfa modulators and their screening by docking studies to determine the binding interaction for the best-fit conformations in the binding site of the ERα receptor. Based on the results of docking studies, the selected ligands reveal the all-important functional groups of the ligands that interact with active amino acid residues in the targeted cavity. Which, if persist in molecules may elicit the desired response in vitro. Amongst the designed derivatives, a ligand which shown better binding energy comparable with standard, Raloxifene. Whereas ligand B60, 59, 65 were found to interact suitably with the active amino acid residues in the targeted cavity that are reported to be involved in interaction with the standard. From the present results, we conclude that designed derivatives have the potential to modulate ERα receptor effectively which can be synthesized and tested for their effectivity, in vitro and in vivo against breast cancer.
Keywords
References
Osz, J.; Brelivet, Y.; Peluso-LItis, C.; Cura, V.; Eiler, S.; Ruff, M.; Bourguet, W.; Rochel, N.; Moras, D. Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors. Proc. Natl. Acad. Sci., USA 2012, 109(10), E588-594.
Choi, K.C.; Jeung, E.B. The biomarker and endocrine disruptors in mammals. J Reprod Dev., 2003, 49(5), 337-345.
Mangelsdorf, D.J.; Thummel, C.; Beato, M.; Herrlich, P.; Schutz, G.; Umesono, K.; Blumberg , B.; Kastner, P.; Mark, M.; Chambon, P.; Evans, R.M. The nuclear receptor superfamily. The second decade. Cell., 1995, 83(6), 835–839.
Pettersson, K.; Gustafsson, J.A. Role of estrogen receptor beta in estrogen action. Annu Rev Physiol., 2001, 63(1), 165–192.
Kuiper, G.G.J.M.; Enmark, E.; Pelto-Huikko, M.; Nilsson, S.; Gustafsson, J. A. Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc. Natl. Acad. Sci. USA., 1996, 93(12), 5925–5930.
Tsai, M.J.; O’Malley, B.W. Molecular mechanisms of action of steroid:thyroid receptor superfamily members. Annu. Rev. Biochem., 1994, 63(1), 451–486.
Evans, R.M. The steroid and thyroid hormone superfamily, Science.1988, 240(4854), 889–895.
Bocchinfuso, W.P.; Korach, K.S. Mammary gland development and tumorigenesis in estrogen receptor knockout mice. J Mammary Gland Biol Neoplasia., 1997, 2(4), 323–334.
Bocchinfuso, W.P.; Lindzey, J.K.; Hewitt, S.C.; Clark, J.A.; Myers, P.H.; Cooper, R.; Korach, K.S. Induction of mammary gland development in estrogen receptor-_ knockout mice. Endocrinology., 2000, 141(8), 2982–2994.
Lee HR, Hwang KA, Park MA, Yi BR, Jeung EB, Choi KC. Treatment with bisphenol A and methoxychlor results in the growth of human breast cancer cells and alteration of the expression of cell cycle-related genes, cyclin D1 and p21, via an estrogen receptor-dependent signaling pathway. Int J Mol Med 2012; 29(5): 883-890.
Weigel NL, Moore NL. Cyclins, cyclin dependent kinases, and regulation of steroid receptor action. Mol Cell Endocrinol 2007; 265-266: 157-161.
Gruber, C.J.; Tschugguel,W.; Schneeberger, C.; Huber, J.C. Production and action of estrogens. N Engl J Med., 2002, 346(5), 340–352.
Swedenborg E, Power KA, Cai W, Pongratz I, Ruegg J.Regulation of estrogen receptor beta activity and implications in health and disease. Cell Mol Life Sci 2009; 66(24): 3873-3894.
Duffy, M.J. Estrogen receptors: Role in Breast Cancer. Critical Reviews in Clinical Laboratory Sciences., 2006, 43(4):325–347.
Liehr, J.G. Genotoxicity of the steroidal estrogens oestrone and oestradiol: Possible mechanisms of uterine and mammary cancer development. Hum Reprod Update., 2001, 7, 273–281.
Fentiman, I.S. Oral contraceptives, hormone replacement therapy and breast cancer. Int J Clin Pract., 2002, 56(10), 755–759.
Berai, V.; Banks, E.; Reeves, G. Evidence from randomised trials on the long-term effects of hormone replacement therapy. Lancet., 2002, 360(9337), 942–944.
Pike, M.C.; Spicer, D.M.; Dahmoush, L.; Press, M.F. Estrogens, progestogens, normal breast cell proliferation and breast cancer risk. Epidemiol Rev., 1993, 15(1), 17–35.
Clemons, M.; Goss, P. Estrogens and risk of breast cancer. N Engl J Med., 2001, 344(4), 276–285.
Dahlman-Wright, K.; Cavailles, V.; Fuqua, S.A.; Jordan, V.C.; Katzenellenbogen, J.A.; Korach, K.S.; Maggi, A.; Muramatsu, M.; Parker, M.G.; Gustafsson, J.A. International union of pharmacology. LXIV. Estrogen receptors. Pharmacol Rev., 2006, 58(4), 773–81.
Hughes ZA, Liu F, Marquis K, Muniz L, Pangalos MN, Ring RH, Whiteside GT, Brandon NJ. Estrogen receptor neurobiology and its potential for translation into broad spectrum therapeutics for CNS disorders. Curr Mol Pharmacol 2009; 2(3): 215-236.
Xiao J, Wang NL, Sun B, Cai GP. Estrogen receptor mediates the effects of pseudoprotodiocsin on adipogenesis in 3T3-L1 cells. Am J Physiol Cell Physiol 2010; 299(1): C128-138.
Heldring, N.; Pike, A.; Andersson, S.; Matthews, J.; Cheng, G.; Hartman, J.; Tujague, M.; Ström, A.; Treuter, E.; Warner, M.; Gustafsson, J.Å. Estrogen receptors: how do they signal and what are their targets? Physiol Rev., 2007, 87(3), 905–31.
Kuiper, G.G.; Enmark, E.; Pelto-Huikko, M.; Nilsson, S.; Gustafsson, J.A. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA., 1996, 93(12), 5925–30.
Ilaria, P.; Carlotta, G.; John, A. K.; Filippo, M. Estrogen receptors alpha (ERa) and beta (ERb): Subtype-selective ligands and clinical potential. Steroids., 2014, 1-17.
Yoko, O.; Hirotaka, I. Clinical significance of estrogen receptor-β in breast. Cancer Sci., 2015,
-7.
Hye-Rim, L.; Tae-Hee, K.; Kyung-C, Choi. Functions and physiological roles of two types of estrogen receptors, ERα and ERβ, identified by estrogen receptor knockout mouse. Lab Anim Res., 2012, 28(2), 71-76.
Jensen, E.V.; Jacobson, H.I. Basic guides to the mechanism of estrogen action. Recent Progress Horm Res., 1962, 18, 387–414.
Welboren WJ, Sweep FC, Span PN, Stunnenberg HG. Genomic actions of estrogen receptor alpha: what are the targets and how are they regulated? Endocr Relat Cancer 2009; 16(4): 1073-1089.
Green, S.; Walter, P.; Kumar, V.; Krust, A.; Bornert, J.M.; Argos, P.; Chambon, P. Human estrogen receptor cDNA: Sequence expression and homology to v-erb-A. Nature., 1986, 320, 134–139.
Kuiper, G.G.J.M.; Enmark, E.; Pelto-Huikko, M.; Nilsson, S.; Gustafsson, J.A. Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA., 1996, 93(12), 5925–5930.
Mosselman, S.; Polman, J.; Dijkema, R. Identification and characterization of a novel human estrogen receptor. FEBS Lett., 1996, 392(1), 49–53.
Jaffe, A.B.; Toran-Allerand, C.D.; Greengard, P.; Gandy, S.E. Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. J Biol Chem.,1994, 269(18), 13065-13068.
Kong EH, Pike AC, Hubbard RE. Structure and mechanism of the oestrogen receptor. Biochem Soc Trans 2003; 31(Pt 1): 56-59.
Skafar DF, Zhao C. The multifunctional estrogen receptor-alpha F domain. Endocrine 2008; 33(1): 1-8.
Stephen, M.; Darshan, S.; Sonia, L.P.; John, A. A. Selective estrogen receptor modulators: tissue specificity and clinical utility. Dove press Journal., 2014, 1437-1452.
Wenlin, S.; Myles, B. Advances in estrogen receptor biology:prospects for improvement in targeted breast cancer therapy. Breast. Cancer. Res., 2004, 1, 39-52.
Geserick C, Meyer HA, Haendler B. The role of DNA response elements as allosteric modulators of steroid receptor function. Mol Cell Endocrinol 2005; 236(1-2): 1-7.
Kong, E.H.; Pike, A.C.; Hubbard, R.E. Structure and mechanism of estrogen receptor. Biochem. Soc. Trans., 2003, 31, 56-9.
Geserickk, C.; Meyer, H.A.; Haendler, B. The role of DNA response element as allosteric modulator of steroid receptor function. Mol. Cell. Endocrinol., 2005, 12, 1-7.
Edwards DP. The role of coactivators and corepressors in the biology and mechanism of action of steroid hormone receptors. J Mammary Gland Biol Neoplasia 2000; 5(3): 307-324.
Beliakoff J.; Whitesell L. Hsp90: an emerging target for breast cancer therapy. Anticancer Drugs., 2004, 15(7), 651-662.
Edwards, D.P. The role of coactivator and corepressors in the biology and mechanism of action steroid hormone receptors. J .Mammary. Gland. Biol. Neoplasia., 2000, 5(3), 307-324.
Resnick, S.M.; Maki, P.M.; Golski, S.; Kraut, M.A.; Zonderman, A.B. Effects of estrogen replacement therapy on PET cerebral blood flow and neu- ropsychological performance. Horm Behav., 1998, 34(2), 171–182.
Mosselman, S.; Polman, J.; Dijkema, R. Identification and characterization of a novel human estrogen receptor. FEBS Lett., 1996, 392(1), 49–53.
Fisher, B.; Costantino, J.P.; Wickerham, D.L. Tamoxifen for prevention of breast cancer: current status of the national surgical adjuvant breast and bowel projects p-1 study. J. Natl. Cancer Inst., 2005, 97, 1652-1662.
Ettinger,B.; Black, D.M.; Mitlak, B.H. Reduction of veretebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA., 1999, 282(7), 637-645.
Vogel, V.G.; Costantino, J.P.; Wickerham, D.L. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA., 2006, 295(23), 2727-2741.
Fisher, B.; Costantino, J.P.; Wickerham, D.L.; et al. Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project p-1 study. J Natl Cancer Inst., 1998, 90(18), 1371–88.
Vastag, B. Raloxifene prevails in STAR trial, may face easier road to acceptance than previous drugs. J Natl Cancer Inst., 2006, 98(11), 733–735.
Stefanick, ML. Risk-benefit profiles of raloxifene for women. N Engl J Med., 2006, 355, 190–192.
Jordan, V.C.; Gapstur, S.; Morrow, M. Selective estrogen receptor modulation and reduction in risk of breast cancer, osteoporosis, and coronary heart disease. J Natl Cancer Inst., 2001, 93(19), 1449–57.
Bernstein, L.; Deapen, D.; Cerhan, J.R.; et al. Tamoxifen therapy for breast cancer and endometrial cancer risk. J Natl Cancer Inst., 1999, 91(19), 1654–62.
Wu, C.J.; Peng, Y.J.; Yu, M.H.; Chen, C.H. Secretory endometrial adenocarcinoma in a tamoxifen user with breast cancer after menopause. Taiwan J Obstet Gynecol., 2007, 46(1), 88–90.
Wang, P.H.; Chao, H.T. A reconsideration of tamoxifen use for breast cancer. Taiwan J Obstet Gynecol., 2007, 46(2), 93–5.
Chen, P.; Yang, C.C.; Chen, Y.J.; Wang, P.H. Tamoxifen-induced endometrial cancer. Eur J Gynaecol Oncol., 2003, 24(2), 135–7.
Vogel, V.G. The NSABP study of Tamoxifen and Raloxifen (STAR) trial. Expert Rev. Anticancer Ther., 2009, 9(1), 51—60.
Komm, B.S. A new approach to menopausal therapy: the tissue selective estrogen complex. Reprod Sci., 2008, 15(10), 984–992.
71)Berrodin, T.J.; Chang, K.C.; Komm, B.S.; Freedman, L.P.; Nagpal, S. Differential biochemical and cellular actions of Premarin estrogens: distinct pharmacology of bazedoxifene-conjugated estrogens combination. Mol Endocrinol., 2009, 23(1), 74–85.
Kharode, Y.; Bodine, P.V.; Miller, C.P.; Lyttle, C.R.; Komm, B.S. The pairing of a selective estrogen receptor modulator, bazedoxifene, with conjugated estrogens as a new paradigm for the treatment of menopausal symptoms and osteoporosis prevention. Endocrinology., 2008, 149(12), 6084–6091.
Riggs, B.L.; Hartmann, L.C. Selective estrogen-receptor modulators – mechanisms of action and application to clinical practice. N Engl J Med.,2003, 348(7), 618–629.
Andrzej, M.; Brzozowski,k.; Ashley, C.W.; Pike, k.; Zbigniew, D.; Roderick, E.; Hubbard, T. B.; Owe, E.; Lars, O.; Geoffrey, L.G.; Jan-A, k. G.; Mats, C. Molecular basis of agonism and antagonismin the oestrogen receptor. NATURE., 1997, 389(6652), 753-758.
Dube, P. N.; Chatpalliwar, V. A. 3, 5-Diphenylpyrazolylethanone Derivatives as Selective Estrogen Receptor Modulators: Design, Synthesis, Biological Evaluation and Docking Analysis. Indo Global Journal of Pharmaceutical Sciences., 2020, 10(1), 25-32.
Miller, P. D.; Chines, A. A.; Christiansen, C. Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of randomized, double blind, placebo, and active-controlled study. J. Bone Miner. Res., 2008, 23(4), 525-535.
Refbacks
- There are currently no refbacks.
Copyright (c) 2021 Research and Reviews: A Journal of Pharmaceutical Science