Abstract
Nuclear receptor drug discovery has been an area of increased interest in recent years. These receptors are attractive pharmacotherapeutic targets due to their omnipresent role in gene transcription that controls several biological processes, including cell proliferation, reproductive functions, and metabolism. Nuclear receptor modulators are unique intracellular messengers in that they must possess certain chemical structure characteristics and/or physicochemical properties in order to be transported or pass through the cell and/or nuclear membranes to reach the receptor in the nucleus. Receptor modulation is inherently contingent upon ligand-receptor binding and, by extension, ligand-receptor interactions. These interactions are based on intermolecular bonding forces, including hydrogen bonds, hydrophobic bonds, and other interactions. Stereochemical considerations and steric effects have also been shown to influence these interactions. Ligand-receptor binding can be either strengthened or weakened by modifying the chemical functional groups based on structure-activity relationship studies. In this chapter, we will explore various chemical fundamentals of ligand-receptor binding and probe the chemical considerations needed in drug discovery for nuclear receptors.
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References
Caboni L, Lloyd DG. Beyond the ligand-binding pocket: targeting alternate sites in nuclear receptors. Med Res Rev. 2013;33(5):1081–118. https://doi.org/10.1002/med.21275.
Abelian A, Dybek M, Wallach J, Gaye B, Adejare A. Pharmaceutical chemistry. Remington: the science and practice of pharmacy. 23rd ed. Cambridge, MA: Academic Press, Elsevier; 2020.
Ates-Alagoz Z, Adejare A. Prodrugs. Remington: the science and practice of pharmacy. 23rd ed. Cambridge, MA: Academic Press, Elsevier; 2020.
El-Gendy BEM, Adejare A. Membrane permeability related and physicochemical properties of a novel gamma-secretase inhibitor. Int J Pharm. 2004;280:47–55.
Elufioye TO, Adejare A. Pharmaceutical profiling. Remington: the science and practice of pharmacy. 23rd ed. Cambridge, MA: Academic Press, Elsevier; 2020.
Adeniji A, Adejare A. Chemical and physical characterization of potential new chemical entity. Preclinical development handbook. Wiley; 2008. p. 211–25.
Burris TP, Solt LA, Wang Y, et al. Nuclear receptors and their selective pharmacologic modulators. Pharmacol Rev. 2013;65(2):710–78. https://doi.org/10.1124/pr.112.006833.
Patrick GL. An introduction to medicinal chemistry. 5th ed. Oxford, UK: Oxford University Press; 2013.
Sever R, Glass CK. Signaling by nuclear receptors. Cold Spring Harb Perspect Biol. 2013;5(3):a016709. https://doi.org/10.1101/cshperspect.a016709.
Lampe J. Case studies in modern drug discovery and development. Am J Health Syst Pharm. 2013;70(9):821. https://doi.org/10.1093/ajhp/70.9.821.
Grese TA, Cho S, Finley DR, et al. Structure−activity relationships of selective estrogen receptor modulators: modifications to the 2-arylbenzothiophene core of raloxifene. J Med Chem. 1997;40(2):146–67. https://doi.org/10.1021/jm9606352.
Suino-Powell K, Xu Y, Zhang C, et al. Doubling the size of the glucocorticoid receptor ligand binding pocket by deacylcortivazol. Mol Cell Biol. 2008;28(6):1915–23. https://doi.org/10.1128/MCB.01541-07.
Mukherjee S, Date A, Patravale V, et al. Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety. Clin Interv Aging. 2006;1(4):327–48. https://doi.org/10.2147/ciia.2006.1.4.327.
Mueller SO, Hall JM, Swope DL, et al. Molecular determinants of the stereoselectivity of agonist activity of Estrogen Receptors (ER) α and β. J Biol Chem. 2003;278(14):12255–62. https://doi.org/10.1074/jbc.M203578200.
Ai N, Krasowski MD, Welsh WJ, et al. Understanding nuclear receptors using computational methods. Drug Discov Today. 2009;14(9):486–94. https://doi.org/10.1016/j.drudis.2009.03.003.
Sonoda MT, MartÃnez L, Webb P, et al. Ligand dissociation from estrogen receptor is mediated by receptor dimerization: evidence from molecular dynamics simulations. Mole Endocrinol. 2008;22(7):1565–78. https://doi.org/10.1210/me.2007-0501.
Chen Z, Chen H, Zhang Z, et al. Discovery of novel liver X receptor inverse agonists as lipogenesis inhibitors. Eur J Med Chem. 2020;206:112793. https://doi.org/10.1016/j.ejmech.2020.112793.
El-Gendy BEM, Goher SS, Hegazy LS, et al. Recent advances in the medicinal chemistry of liver X receptors. J Med Chem. 2018;61(24):10935–10,956. https://doi.org/10.1021/acs.jmedchem.8b00045.
Annicotte JS, Schoonjans K, Auwerx J. Expression of the liver X receptor alpha and beta in embryonic and adult mice. The Anatomical record. 2004;277A(2):312–6. https://doi.org/10.1002/ar.a.20015.
Tice CM, Noto PB, Fan KY, et al. The medicinal chemistry of Liver X Receptor (LXR) modulators. J Med Chem. 2014;57(17):7182–205. https://doi.org/10.1021/jm500442z.
Janowski BA, Grogan MJ, Jones SA, et al. Structural requirements of ligands for the oxysterol liver X receptors LXR and LXR. Proc Natl Acad Sci – PNAS. 1999;96(1):266–71. https://doi.org/10.1073/pnas.96.1.266.
Janowski BA, Willy PJ, Devi TR, et al. An oxysterol signalling pathway mediated by the nuclear receptor LXRα. Nature (London). 1996;383(6602):728–31. https://doi.org/10.1038/383728a0.
Michael L, Schkeryantz J, Burris T. The pharmacology of LXR. Mini Rev Med Chem. 2005;5(8):729–40. https://doi.org/10.2174/1389557054553767.
Williams S, Bledsoe RK, Collins JL, et al. X-ray crystal structure of the liver X receptor β ligand binding domain. J Biol Chem. 2003;278(29):27138–27,143. https://doi.org/10.1074/jbc.m302260200.
Färnegårdh M, Bonn T, Sun S, et al. The three-dimensional structure of the liver X receptor β reveals a flexible ligand-binding pocket that can accommodate fundamentally different ligands. J Biol Chem. 2003;278(40):38821–38,828. https://doi.org/10.1074/jbc.M304842200.
Zheng Y, Zhuang L, Fan KY, et al. Discovery of a novel, orally efficacious Liver X Receptor (LXR) β agonist. J Med Chem. 2016;59(7):3264–71. https://doi.org/10.1021/acs.jmedchem.5b02029.
Rodriguez CR, Alvarez LD, Dansey MV, et al. Fluorinated oxysterol analogues: synthesis, molecular modelling and LXRβ activity. J Steroid Biochem Mol Biol. 2017;165(Pt B):268–76. https://doi.org/10.1016/j.jsbmb.2016.07.001.
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Abelian, A., Adejare, A. (2021). Chemical Considerations in Discovery of Receptor Modulators. In: Badr, M.Z. (eds) Nuclear Receptors. Springer, Cham. https://doi.org/10.1007/978-3-030-78315-0_4
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DOI: https://doi.org/10.1007/978-3-030-78315-0_4
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