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Current Pharmaceutical Design

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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Research Article

Computational Screening of Some Phytochemicals to Identify Best Modulators for Ligand Binding Domain of Estrogen Receptor Alpha

Author(s): Veerachamy Alagarsamy*, Pottabathula Shyam Sundar, Viswas Raja Solomon*, Sankaranarayanan Murugesan, Mohammed Muzaffar-Ur-Rehman, Vishaka Sumant Kulkarni, Mohaideen Thasthagir Sulthana, Bandi Narendhar and Govindraj Sabarees

Volume 30, Issue 20, 2024

Published on: 02 May, 2024

Page: [1599 - 1609] Pages: 11

DOI: 10.2174/0113816128287431240408045732

Price: $65

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Abstract

Objective: The peculiar aim of this study is to discover and identify the most effective and potential inhibitors against the most influential target ERα receptor by in silico studies of 45 phytochemicals from six diverse ayurvedic medicinal plants.

Methods: The molecular docking investigation was carried out by the genetic algorithm program of AutoDock Vina. The molecular dynamic (MD) simulation investigations were conducted using the Desmond tool of Schrödinger molecular modelling. This study identified the top ten highest binding energy phytochemicals that were taken for drug-likeness test and ADMET profile prediction with the help of the web-based server QikpropADME.

Results: Molecular docking study revealed that ellagic acid (-9.3 kcal/mol), emodin (-9.1 kcal/mol), rhein (-9.1 kcal/mol), andquercetin (-9.0 kcal/mol) phytochemicals showed similar binding affinity as standard tamoxifen towards the target protein ERα. MD studies showed that all four compounds possess comparatively stable ligand-protein complexes with ERα target compared to the tamoxifen-ERα complex. Among the four compounds, phytochemical rhein formed a more stable complex than standard tamoxifen. ADMET studies for the top ten highest binding energy phytochemicals showed a better safety profile.

Conclusion: Additionally, these compounds are being reported for the first time in this study as possible inhibitors of ERα for treating breast cancer, according to the notion of drug repurposing. Hence, these phytochemicals can be further studied and used as a parent core molecule to develop innovative lead molecules for breast cancer therapy.

« Previous Next »
[1]
American Cancer Society. Cancer Facts and Figures 2023. Atlanta, Ga: American Cancer Society 2023.
[2]
Cancer Statistics Center. Available from: https://cancerstatisticscenter.cancer.org/
[3]
Current and future burden of breast cancer. 2020. Available from: https://www.iarc.who.int/news-events/current-and-future-burden-of-breast-cancer-global-statistics-for-2020-and-2040/
[4]
Chen P, Li B, Ou-Yang L. Role of estrogen receptors in health and disease. Front Endocrinol 2022; 13: 839005.
[http://dx.doi.org/10.3389/fendo.2022.839005] [PMID: 36060947]
[5]
Faltas CL, LeBron KA, Holz MK. Unconventional estrogen signaling in health and disease. Endocrinology 2020; 161(4): bqaa030.
[http://dx.doi.org/10.1210/endocr/bqaa030] [PMID: 32128594]
[6]
Fuentes N, Silveyra P. Estrogen receptor signaling mechanisms. Adv Protein Chem Struct Biol 2019; 116: 135-70.
[http://dx.doi.org/10.1016/bs.apcsb.2019.01.001]
[7]
Shang Y. Molecular mechanisms of oestrogen and SERMs in endometrial carcinogenesis. Nat Rev Cancer 2006; 6(5): 360-8.
[http://dx.doi.org/10.1038/nrc1879] [PMID: 16633364]
[8]
Bolger R, Wiese TE, Ervin K, Nestich S, Checovich W. Rapid screening of environmental chemicals for estrogen receptor binding capacity. Environ Health Perspect 1998; 106(9): 551-7.
[http://dx.doi.org/10.1289/ehp.98106551] [PMID: 9721254]
[9]
Delfosse V, Maire A, Balaguer P, Bourguet W. A structural perspective on nuclear receptors as targets of environmental compounds. Acta Pharmacol Sin 2015; 36(1): 88-101.
[http://dx.doi.org/10.1038/aps.2014.133] [PMID: 25500867]
[10]
Arnold M, Morgan E, Rumgay H, et al. Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast 2022; 66: 15-23.
[http://dx.doi.org/10.1016/j.breast.2022.08.010] [PMID: 36084384]
[11]
Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med 2006; 354(3): 270-82.
[http://dx.doi.org/10.1056/NEJMra050776] [PMID: 16421368]
[12]
Helguero LA, Faulds MH, Gustafsson JÅ, Haldosén LA. Estrogen receptors alfa (ERα) and beta (ERβ) differentially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line HC11. Oncogene 2005; 24(44): 6605-16.
[http://dx.doi.org/10.1038/sj.onc.1208807] [PMID: 16007178]
[13]
Murphy LC, Peng B, Lewis A, et al. Inducible upregulation of oestrogen receptor-β1 affects oestrogen and tamoxifen responsiveness in MCF7 human breast cancer cells. J Mol Endocrinol 2005; 34(2): 553-66.
[http://dx.doi.org/10.1677/jme.1.01688] [PMID: 15821116]
[14]
Treeck O, Lattrich C, Springwald A, Ortmann O. Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells. Breast Cancer Res Treat 2010; 120(3): 557-65.
[http://dx.doi.org/10.1007/s10549-009-0413-2] [PMID: 19434490]
[15]
Sun J, Chu YF, Wu X, Liu RH. Antioxidant and antiproliferative activities of common fruits. J Agric Food Chem 2002; 50(25): 7449-54.
[http://dx.doi.org/10.1021/jf0207530] [PMID: 12452674]
[16]
Taraphdar AK, Roy M, Bhattacharya R. Natural products as inducers of apoptosis: Implication for cancer therapy and prevention. Curr Sci 2001; 1387-96.
[17]
Pal SK, Shukla Y. Herbal medicine: Current status and the future. Asian Pac J Cancer Prev 2003; 4(4): 281-8.
[PMID: 14728584]
[18]
Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov 2005; 4(3): 206-20.
[http://dx.doi.org/10.1038/nrd1657] [PMID: 15729362]
[19]
Saklani A, Kutty SK. Plant-derived compounds in clinical trials. Drug Discov Today 2008; 13: 161-71.
[http://dx.doi.org/10.1016/j.drudis.2007.10.010]
[20]
Hartman J, Lindberg K, Morani A, Inzunza J, Ström A, Gustafsson JÅ. Estrogen receptor beta inhibits angiogenesis and growth of T47D breast cancer xenografts. Cancer Res 2006; 66(23): 11207-13.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-0017] [PMID: 17145865]
[21]
Swaby RF, Sharma CGN, Jordan VC. SERMs for the treatment and prevention of breast cancer. Rev Endocr Metab Disord 2007; 8(3): 229-39.
[http://dx.doi.org/10.1007/s11154-007-9034-4] [PMID: 17440819]
[22]
Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer 2009; 9(9): 631-43.
[http://dx.doi.org/10.1038/nrc2713] [PMID: 19701242]
[23]
Suetsugi M. Flavone and isoflavone phytoestrogens are agonists of estrogen related receptors. Mol Can Res 2009; 981-91.
[24]
Zand RSR, Jenkins DJA, Diamandis EP. Steroid hormone activity of flavonoids and related compounds. Breast Cancer Res Treat 2000; 62(1): 35-49.
[http://dx.doi.org/10.1023/A:1006422302173] [PMID: 10989984]
[25]
Grande F, Rizzuti B, Occhiuzzi MA, et al. Identification by molecular docking ofhomoisoflavones from leopoldia comosa as ligands of estrogen receptors. Molecules 2018; 23(4): 894.
[http://dx.doi.org/10.3390/molecules23040894] [PMID: 29649162]
[26]
Jameera Begam A, Jubie S, Nanjan MJ. Estrogen  receptor  agonists/antagonists in breast cancer therapy: A critical review. Bioorg Chem 2017; 71: 257-74.
[http://dx.doi.org/10.1016/j.bioorg.2017.02.011] [PMID: 28274582]
[27]
Ng HW, Zhang W, Shu M, et al. Competitive molecular docking approach for predicting estrogen receptor subtype α agonists and antagonists. BMC Bioinf 2014; 15(S11): S4.
[http://dx.doi.org/10.1186/1471-2105-15-S11-S4] [PMID: 25349983]
[28]
Chakraborty S, Levenson AS, Biswas PK. Structural insights into Resveratrol’s antagonist and partial agonist actions on estrogen receptor α. BMC Struct Biol 2013; 13(1): 27.
[http://dx.doi.org/10.1186/1472-6807-13-27] [PMID: 24160181]
[29]
Surjushe A, Vasani R, Saple DG. Aloe vera: A short review. Indian J Dermatol 2008; 53(4): 163-6.
[http://dx.doi.org/10.4103/0019-5154.44785] [PMID: 19882025]
[30]
Hu Y, Yang L, Lai Y. Recent findings regarding the synergistic effects of emodin and its analogs with other bioactive compounds: Insights into new mechanisms. Biomed Pharmacother 2023; 162: 114585.
[http://dx.doi.org/10.1016/j.biopha.2023.114585] [PMID: 36989724]
[31]
Baliga MS, Dsouza JJ. Amla (Emblica officinalis Gaertn), a wonder berry in the treatment and prevention of cancer. Eur J Cancer Prev 2011; 20(3): 225-39.
[http://dx.doi.org/10.1097/CEJ.0b013e32834473f4] [PMID: 21317655]
[32]
Bonte J. Chemoprevention of breast cancer. Eur J Cancer Prev 1993; 2(3): 141-6.
[http://dx.doi.org/10.1097/00008469-199311000-00021] [PMID: 8298444]
[33]
Ahmad N, Basri AM, Taha H. A review on the pharmacological activities and phytochemicals of Alpinia officinarum (Galangal) extracts derived from bioassay-guided fractionation and isolation. Pharmacogn Rev 2017; 11(21): 43-56.
[http://dx.doi.org/10.4103/phrev.phrev_55_16] [PMID: 28503054]
[34]
Van HT, Thang TD, Luu TN, Doan VD. An overview of the chemical composition and biological activities of essential oils from Alpinia genus (Zingiberaceae). RSC Advances 2021; 11(60): 37767-83.
[http://dx.doi.org/10.1039/D1RA07370B] [PMID: 35498079]
[35]
Prakash NS, Sundaram R, Mitra SK. Shatavarins (containing Shatavarin IV) with anticancer activity from the roots of Asparagus racemosus. Indian J Pharmacol 2012; 44(6): 732-6.
[http://dx.doi.org/10.4103/0253-7613.103273] [PMID: 23248403]
[36]
Joshi GP, Rawat MS, Bisht VK, Negi JS, Singh P. Chemical constituents of Asparagus. Pharmacogn Rev 2010; 4(8): 215-20.
[http://dx.doi.org/10.4103/0973-7847.70921] [PMID: 22228964]
[37]
Park SH, Kim M, Lee S. Therapeutic potential of natural products in treatment of cervical cancer: A review. Nutrients 2021; 13(1): 1-154.
[http://dx.doi.org/10.3390/nu13010154]
[38]
Henamayee S, Banik K, Sailo BL, et al. Therapeutic emergence of rhein as a potential anticancer drug: A review of its molecular targets and anticancer properties. Molecules 2020; 25(10): 2278.
[http://dx.doi.org/10.3390/molecules25102278] [PMID: 32408623]
[39]
Hasan MR, Alotaibi BS, Althafar ZM, Mujamammi AH, Jameela J. An update on the therapeutic anticancer potential of Ocimum sanctum L.: “Elixir of Life”. Molecules 2023; 28(3): 1193.
[http://dx.doi.org/10.3390/molecules28031193] [PMID: 36770859]
[40]
Pattanayak P, Behera P, Das D, Panda S. Ocimum sanctum Linn. A reservoir plant for therapeutic applications: An overview. Pharmacogn Rev 2010; 4(7): 95-105.
[http://dx.doi.org/10.4103/0973-7847.65323] [PMID: 22228948]
[41]
Baliga MS, Jimmy R, Thilakchand KR, et al. Ocimum sanctum L. (Holy Basil or Tulsi) and its phytochemicals in the prevention and treatment of cancer. Nutr Cancer 2013; 65(sup1): 26-35.
[http://dx.doi.org/10.1080/01635581.2013.785010] [PMID: 23682780]
[42]
Krieger E. New ways to boost molecular dynamics simulations. J Comput Chem 2015; 36(13): 996-1007.
[43]
Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31(2): 455-61.
[http://dx.doi.org/10.1002/jcc.21334] [PMID: 19499576]
[44]
Hollingsworth SA, Dror RO. Molecular dynamics simulation for all. Neuron 2018; 99(6): 1129-43.
[http://dx.doi.org/10.1016/j.neuron.2018.08.011] [PMID: 30236283]
[45]
Trond I, Ole JH. Time reversible molecular dynamics algorithms with holonomic bond constraints in the NPH and NPT ensembles using molecular scaling. J Chem Phys 2010; 132(15): 154106.
[http://dx.doi.org/10.1063/1.3363609]

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