Homology in the Binding Patterns of Human and Rat Androgen Receptors with various Ligands

Jump To References Section


  • Department of Zoology, Sacred Heart College (Autonomous), Thevara - 682013, Kochi, Kerala
  • Department of Zoology, Mar Athanasius College (Autonomous), Kothamangalam - 686666, Kerala
  • Department of Zoology, Marian College of Arts and Science, Kazhakuttom, Trivandrum - 695582, Kerala




Androgen Agonist, Androgen Receptors, Biovia Discovery Studio, In-Silico Docking, Laboratory Animal Models


Scientists routinely use in-vivo animal experiments to study the reproductive and endocrine effects of various chemicals in humans. Rats are being used as the most suitable animal model for such investigations. Use of animal models to envisage the mode of action of a particular chemical in humans is questionable unless we can explain the binding similarities. In this study, an in-silico docking was employed to visualise if androgens and their agonists bind with androgen receptors of humans and rats in a similar pattern using BIOVIA Discovery Studio 2018. Amino acid residues involved in bond formation, nature of bonding, LibDock score and bond distances were calculated to compare the binding affinities. It was found that ASN 705, GLN 711, ARG 752 and THR 877 were the major amino acid residues in hydrogen bonding of selected ligands with both human and rat androgen receptors. Thus, the present study answers numerous questions that may arise while selecting rats as laboratory animal models to validate the androgenic effects of chemicals in humans.


Download data is not yet available.


Metrics Loading ...



Li J, Al-Azzawi F. Mechanism of androgen receptor action. Maturitas. 2009; 63(2):142-8. https://doi.org/10.1016/j. maturitas.2009.03.008. PMid:19372015.

Gao W, Bohl CE, Dalton JT. Chemistry and Structural Biology of Androgen Receptor. Chem Rev. 2005; 105(1):3352-70. https:// doi.org/10.1021/cr020456u. PMid:16159155 PMCid:PMC2096617.

Christiansen AR, Lipshultz LI, Hotaling JM, Pastuszak AW. Selective androgen receptor modulators: The future of androgen therapy? Transl Androl Urol. 2020; 9(Suppl 2):S135-48. https://doi.org/10.21037/tau.2019.11.02. PMid:32257854 PMCid:PMC7108998.

Zhi L, Martinborough E. Chapter 17. Selective androgen receptor modulators (SARMs). Annu Rep Med Chem. 2001; 36(10):169- 80. https://doi.org/10.1016/S0065-7743(01)36057-8.

Choi SM, Lee B. Comparative safety evaluation of selective androgen receptor modulators and anabolic androgenic steroids. Expert Opin Drug Saf. 2015; 14(11):1773-85. https://doi.org/10.1517/14740338.2015.1094052. PMid:26401842.

Pop A, Drugan T, Gutleb AC, et al. Estrogenic and anti?estrogenic activity of butylparaben, butyl-ated hydroxyanisole, butylated hydroxytoluene and propyl gal-late and their binary mixtures on two estrogen responsive cell lines (T47D-Kbluc, MCF-7). J Appl Toxicol. 2018; 38(7):944-57. https://doi.org/10.1002/jat.3601. PMid:29460325.

Pop A, Drugan T, Gutleb AC, et al. Individual and combined in vitro (anti)androgenic effects of certain food additives and cosmetic preservatives. Toxicol In Vitro. 2016; 32:269-77. https://doi.org/10.1016/j.tiv.2016.01.012. PMid:26812027.

Hwan GK, Jeong SH, Joon HC, et al, Evaluation of estrogenic and androgenic activity of butylated hydroxyanisole in immature female and castrated rats. Toxicology. 2005; 213(1-2):147-56. https://doi.org/10.1016/j.tox.2005.05.027. PMid:16023279.

Lynch C, Sakamuru S, Huang R, et al. Identifying environmental chemicals as agonists of the androgen receptor by using a quantitative high-throughput screening platform. Toxicology. 2017; 385:48-58. https://doi.org/10.1016/j.tox.2017.05.001. PMid:28478275 PMCid: PMC6135100.

Schrader TJ, Cooke GM. Examination of selected food additives and organochlorine food contaminants for androgenic activity in vitro. Toxicol Sci. 2000; 53(2):278-88. https://doi.org/10.1093/toxsci/53.2.278. PMid:10696776.

Orton F, Ermler S, Kugathas S, et al. Mixture effects at very low doses with combinations of anti-androgenic pesticides, antioxidants, industrial pollutant and chemicals used in personal care products. Toxicol Appl Pharmacol. 2014; 278(3):201-8. https://doi. org/10.1016/j.taap.2013.09.008. PMid:24055644.

Parks LG, Lambright CS, Orlando EF, et al. Masculinization of female mosquitofish in kraft mill effluent- contaminated Fenholloway River water is associated with androgen receptor agonist activity. Toxicol Sci. 2001; 267(62):257-67. https://doi. org/10.1093/toxsci/62.2.257. PMid:11452138.

OECD. OECD Series on Testing and Assessment. OECD Publishing. 2018. https://doi.org/10.1787/9789264304796- en.

Owens JW, Gray LE, Zeiger E, et al. The OECD Program to Validate the Rat Hershberger Bioassay to Screen Compounds for in Vivo Androgen and Antiandrogen Responses: Phase 2 Dose-Response Studies. Environ Health Perspect. 2007; 115(5):671-8. https://doi.org/10.1289/ehp.9666. PMid:17520051 PMCid:PMC1867976.

Freyberger A, Ahr HJ. Development and standardization of a simple binding assay for the detection of compounds with affinity for the androgen receptor. Toxicology. 2004; 195(2-3):113-26. https://doi.org/10.1016/j.tox.2003.09.008. PMid:14751668.

Yamasaki K, Sawaki M, Noda S, et al. Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals. Toxicology. 2004; 195(2-3):177-86. https://doi.org/10.1016/j.tox.2003.09.012. PMid:14751673.

Mansouri K, Kleinstreuer N, Abdelaziz AM, et al. CoMPARA: Collaborative modeling project for androgen receptor activity. Environ Health Perspect. 2020; 128(2):27002. https://doi.org/10.1289/EHP5580. PMid:32074470 PMCid:PMC7064318.

Kleinstreuer NC, Ceger P, Watt ED, et al. Development and Validation of a Computational Model for Androgen Receptor Activity. Chem Res Toxicol. 2017; 30(4):946-64. https://doi.org/10.1021/acs.chemrestox.6b00347. PMid:27933809 PMCid:PMC5396026.

Maria Maddalena Calabretta, Antonia Lopreside Laura Montali LC, Roda A, Michelini and E. A Genetically Encoded Bioluminescence Intracellular Nanosensor for Androgen Receptor Activation Monitoring in 3D cell Models. Sensors (Basel). 2021; 21(3):893. https://doi.org/10.3390/s21030893. PMid:33572727 PMCid:PMC7865915.

Kiani NA, Shang MM, Zenil H, Tegner J. Predictive systems toxicology. Methods Mol Biol. 2018; 1800:535-57. https://doi. org/10.1007/978-1-4939-7899-1_25. PMid:29934910.

Yu M, Lee J, Lee Y, Na D. 2-D chemical structure image-based in silico model to predict agonist activity for androgen receptor. BMC Bioinformatics. 2020; 21(Suppl 5):1-8. https://doi.org/10.1186/s12859-020-03588-1. PMid: 33106158 PMCid:PMC7586653.

Lubahn DB, Joseph DR, Sar M, et al. The human androgen receptor: Complementary deoxyribonucleic acid cloning, sequence analysis and gene expression in prostate. Mol Endocrinol. 1988; 2(12):1265-75. https://doi.org/10.1210/mend-2-12-1265. PMid:3216866.

Yang L, Li W, Zhao Y, Zhong S, et al. Computational Study of Novel Natural Inhibitors Targeting O6-Methylguanine-DNA Methyltransferase. World Neurosurg. 2019; 130:e294-e306. https://doi.org/10.1016/j.wneu.2019.05.264. PMid:31203065.

Habib H, Haider MR, Sharma S, et al. Molecular interactions of vinclozolin metabolites with human estrogen receptors 1GWR-? and 1QKM and androgen receptor 2AM9-?: Implication for endocrine disruption. Toxicol Mech Methods. 2020; 30(5):370-07. https://doi.org/10.1080/15376516.2020.1747123. PMid:32208804.

Sack JS, Kish KF, Wang C, et al. Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone. Proc Natl Acad Sci USA. 2001; 98(9):4904-09. https://doi. org/10.1073/pnas.081565498. PMid:11320241 PMCid:PMC33136.

Farla P, Hersmus R, Geverts B, et al. The androgen receptor ligand-binding domain stabilizes DNA binding in living cells. J Struct Biol. 2004; 147(1):50-61. https://doi.org/10.1016/j.jsb.2004.01.002. PMid:15109605.

Schauwaers K, De Gendt K, Saunders PTK, et al. Loss of androgen receptor binding to selective androgen response elements causes a reproductive phenotype in a knockin mouse model. Proc Natl Acad Sci USA. 2007; 104(12):4961-6. https://doi.org/10.1073/ pnas.0610814104. PMid:17360365 PMCid:PMC1829247.

Claessens F, Verrijdt G, Schoenmakers E, et al. Selective DNA binding by the androgen receptor as a mechanism for hormonespecific gene regulation. J Steroid Biochem Mol Biol. 2001; 76(1-5):23-30. https://doi.org/10.1016/S0960-0760(00)00154-0.

Marhefka CA, Moore BM, Bishop TC, et al. Homology modeling using multiple molecular dynamics simulations and docking studies of the human androgen receptor ligand binding domain bound to testosterone and nonsteroidal ligands. J Med Chem. 2001; 44(11):1729-40. https://doi.org/10.1021/jm0005353. PMid:11356108.

Matias PM, Donner P, Coelho R, et al. 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):26164-71. https://doi.org/10.1074/jbc. M004571200. PMid:10840043.

Weikum ER, Liu X, Ortlund EA. The nuclear receptor superfamily: A structural perspective. Protein Sci. 2018; 27(11):1876-92. https://doi.org/10.1002/pro.3496. PMid:30109749 PMCid:PMC6201731.

Zhou W, Duan M, Fu W, et al. Discovery of novel androgen receptor ligands by structure-based virtual screening and bioassays. Genomics, Proteomics and Bioinformatics. The Authors; 2018; 16(6):416-427. https://doi.org/10.1016/j.gpb.2018.03.007. PMid:30639122 PMCid:PMC6411960.

Sakkiah S, Kusko R, Pan B, et al. Structural changes due to antagonist binding in ligand binding pocket of androgen receptor elucidated through molecular dynamics simulations. Front Pharmacol. 2018; 9:492. https://doi.org/10.3389/fphar.2018.00492. PMid:29867496 PMCid:PMC5962723.




How to Cite

Balachandran, S., Binitha, R. N., & Sunny, F. (2022). Homology in the Binding Patterns of Human and Rat Androgen Receptors with various Ligands. Journal of Endocrinology and Reproduction, 26(1), 35–44. https://doi.org/10.18311/jer/2022/29666



Original Research