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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Phytoestrogens as Potential Antiandrogenic Agents Against Prostate Cancer: An In Silico Analysis

Author(s): Neetu Agrawal*, Somdutt Mujwar, Ahsas Goyal and Jeetendra Kumar Gupta

Volume 19, Issue 1, 2022

Published on: 13 August, 2021

Page: [69 - 78] Pages: 10

DOI: 10.2174/1570180818666210813121431

Price: $65

Abstract

Background: Prostate cancer is the second most common cancer worldwide. The androgen deprivation therapy or castration leads to the recurrence of castration-resistant prostate cancer after some time. Androgen receptor is one of the most promising targets for the treatment of prostate cancer. The health benefits of phytoestrogens led us to explore them for their androgen receptor inhibition potential that may lead to inhibition of initiation and progression of prostate cancer.

Methods: Protein-ligand interaction plays a central role in structure-based drug design, so we screened 23 phytoestrogens for their binding affinity to the androgen receptor using the molecular docking approach. These phytoestrogens were also tested for their ADME and toxicity profiles using the software.

Results: Based on binding affinity, interacting amino acid residues, pharmacokinetics and toxicity profile, four phytoestrogens, namely naringenin, luteolin, hesperetin, and biochanin A were shortlisted as lead molecules.

Conclusion: Therefore, our study has shown that these four phytoestrogens could be promising candidates for further evaluation for prostate cancer treatment or management.

Keywords: Androgen receptor, prostate cancer, molecular docking, phytoestrogens, in silico, ADME.

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[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Taplin, M-E.; Rajeshkumar, B.; Halabi, S.; Werner, C.P.; Woda, B.A.; Picus, J.; Stadler, W.; Hayes, D.F.; Kantoff, P.W.; Vogelzang, N.J.; Small, E.J. Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663. J. Clin. Oncol., 2003, 21(14), 2673-2678.
[http://dx.doi.org/10.1200/JCO.2003.11.102] [PMID: 12860943]
[3]
Jernberg, E.; Bergh, A.; Wikström, P. Clinical relevance of androgen receptor alterations in prostate cancer. Endocr. Connect., 2017, 6(8), R146-R161.
[http://dx.doi.org/10.1530/EC-17-0118] [PMID: 29030409]
[4]
Wang, L.; Song, T.; Wang, X.; Li, J. Discovery and identification of pyrazolopyramidine analogs as novel potent androgen receptor antagonists. Front. Pharmacol., 2018, 9, 864-876.
[http://dx.doi.org/10.3389/fphar.2018.00864] [PMID: 30210333]
[5]
Fujita, K.; Nonomura, N. Role of androgen receptor in prostate cancer: A review. World J. Mens Health, 2019, 37(3), 288-295.
[http://dx.doi.org/10.5534/wjmh.180040] [PMID: 30209899]
[6]
Sharifi, N.; Gulley, J.L.; Dahut, W.L. Androgen deprivation therapy for prostate cancer. JAMA, 2005, 294(2), 238-244.
[http://dx.doi.org/10.1001/jama.294.2.238] [PMID: 16014598]
[7]
Feng, Q.; He, B. Androgen receptor signaling in the development of castration-resistant prostate cancer. Front. Oncol., 2019, 9, 858-867.
[http://dx.doi.org/10.3389/fonc.2019.00858] [PMID: 31552182]
[8]
Bosland, M.C. The role of estrogens in prostate carcinogenesis: a rationale for chemoprevention. Rev. Urol., 2005, 7(Suppl. 3), S4-S10.
[PMID: 16985878]
[9]
Moorthy, H.K.; Laxman Prabhu, G.G.; Venugopal, P. The resurgence of estrogens in the treatment of castration-resistant prostate cancer. Indian J. Urol., 2019, 35(3), 189-196.
[http://dx.doi.org/10.4103/iju.IJU_56_19] [PMID: 31367069]
[10]
Sivoňová, M.K.; Kaplán, P.; Tatarková, Z.; Lichardusová, L.; Dušenka, R.; Jurečeková, J. Androgen receptor and soy isoflavones in prostate cancer. Mol. Clin. Oncol., 2019, 10(2), 191-204.
[PMID: 30680195]
[11]
Sahin, I.; Bilir, B.; Ali, S.; Sahin, K.; Kucuk, O. Soy isoflavones in integrative oncology: Increased efficacy and decreased toxicity of cancer therapy. Integr. Cancer Ther., 2019, 181534735419835310
[http://dx.doi.org/10.1177/1534735419835310] [PMID: 30897972]
[12]
Wang, H.; Li, J.; Gao, Y.; Xu, Y.; Pan, Y.; Tsuji, I.; Sun, Z-J.; Li, X-M. Xeno-oestrogens and phyto-oestrogens are alternative ligands for the androgen receptor. Asian J. Androl., 2010, 12(4), 535-547.
[http://dx.doi.org/10.1038/aja.2010.14] [PMID: 20436506]
[13]
Wu, J.; Liu, S.; Shen, X.; Yang, N.; Liu, Y.; Tsuji, I.; Yamamura, T.; Li, J.; Li, X. Phytoestrogens inhibiting androgen receptor Signal and prostate cancer cell proliferation. Chem. Res. Chin. Univ., 2013, 29, 911-916.
[http://dx.doi.org/10.1007/s40242-013-3123-6]
[14]
Selvaraj, D.; Muthu, S.; Kotha, S.; Siddamsetty, R.S.; Andavar, S.; Jayaraman, S. Syringaresinol as a novel androgen receptor antagonist against wild and mutant androgen receptors for the treatment of castration-resistant prostate cancer: molecular docking, in-vitro and molecular dynamics study. J. Biomol. Struct. Dyn., 2020, 1-14.
[http://dx.doi.org/10.1080/07391102.2020.1778535] [PMID: 31928160]
[15]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[16]
Goodsell, D.S.; Morris, G.M.; Olson, A.J. Automated docking of flexible ligands: applications of AutoDock. J. Mol. Recognit., 1996, 9(1), 1-5.
[http://dx.doi.org/10.1002/(SICI)1099-1352(199601)9:1<1:AID-JMR241>3.0.CO;2-6] [PMID: 8723313]
[17]
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(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[18]
Patisaul, H.B.; Jefferson, W. The pros and cons of phytoestrogens. Front. Neuroendocrinol., 2010, 31(4), 400-419.
[http://dx.doi.org/10.1016/j.yfrne.2010.03.003] [PMID: 20347861]
[19]
Sander, T.; Freyss, J.; von Korff, M.; Rufener, C. DataWarrior: an open-source program for chemistry aware data visualization and analysis. J. Chem. Inf. Model., 2015, 55(2), 460-473.
[http://dx.doi.org/10.1021/ci500588j] [PMID: 25558886]
[20]
Lipinski, C.A. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341.
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]
[21]
Matias, P.M.; Donner, P.; Coelho, R.; Thomaz, M.; Peixoto, C.; Macedo, S.; Otto, N.; Joschko, S.; Scholz, P.; Wegg, A.; Bäsler, S.; Schäfer, M.; Egner, U.; Carrondo, M.A. Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations. J. Biol. Chem., 2000, 275(34), 26164-26171.
[http://dx.doi.org/10.1074/jbc.M004571200] [PMID: 10840043]
[22]
Da Pozzo, E.; Costa, B.; Cavallini, C.; Testai, L.; Martelli, A.; Calderone, V.; Martini, C. The citrus flavanone naringenin protects myocardial cells against age-associated damage. Oxid. Med. Cell. Longev., 2017, 20179536148
[http://dx.doi.org/10.1155/2017/9536148] [PMID: 28386313]
[23]
Lin, Y.; Shi, R.; Wang, X.; Shen, H-M. Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr. Cancer Drug Targets, 2008, 8(7), 634-646.
[http://dx.doi.org/10.2174/156800908786241050] [PMID: 18991571]
[24]
Kim, H.K.; Jeong, T-S.; Lee, M-K.; Park, Y.B.; Choi, M-S. Lipid-lowering efficacy of hesperetin metabolites in high-cholesterol fed rats. Clin. Chim. Acta, 2003, 327(1-2), 129-137.
[http://dx.doi.org/10.1016/S0009-8981(02)00344-3] [PMID: 12482628]
[25]
Booth, N.L.; Piersen, C.E.; Banuvar, S.; Geller, S.E.; Shulman, L.P.; Farnsworth, N.R. Clinical studies of red clover (Trifolium pratense) dietary supplements in menopause: a literature review. Menopause, 2006, 13(2), 251-264.
[http://dx.doi.org/10.1097/01.gme.0000198297.40269.f7] [PMID: 16645539]

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