Abstract
In this chapter we provide an exhaustive overview of the binding modes of bile acid (BA) and non-BA ligands to the nuclear farnesoid X receptor (FXR) and the G-protein bile acid receptor 1 (GPBAR1). These two receptors play a key role in many diseases related to lipid and glucose disorders, thus representing promising pharmacological targets. We pay particular attention to the chemical and structural features of the ligand-receptor interaction, providing guidelines to achieve ligands endowed with selective or dual activity towards the receptor and paving the way to future drug design studies.
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References
Akwabi-Ameyaw A, Bass JY, Caldwell RD et al (2008) Conformationally constrained farnesoid X receptor (FXR) agonists: naphthoic acid-based analogs of GW 4064. Bioorg Med Chem Lett 18(15):4339–4343. https://doi.org/10.1016/j.bmcl.2008.06.073
Akwabi-Ameyaw A, Bass JY, Caldwell RD et al (2009) FXR agonist activity of conformationally constrained analogs of GW 4064. Bioorg Med Chem Lett 19(16):4733–4739. https://doi.org/10.1016/j.bmcl.2009.06.062
Akwabi-Ameyaw A, Caravella JA, Chen L et al (2011) Conformationally constrained farnesoid X receptor (FXR) agonists: alternative replacements of the stilbene. Bioorg Med Chem Lett 21(20):6154–6160. https://doi.org/10.1016/j.bmcl.2011.08.034
Bass JY, Caldwell RD, Caravella JA et al (2009) Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064. Bioorg Med Chem Lett 19(11):2969–2973. https://doi.org/10.1016/j.bmcl.2009.04.047
Bass JY, Caravella JA, Chen L et al (2011) Conformationally constrained farnesoid X receptor (FXR) agonists: heteroaryl replacements of the naphthalene. Bioorg Med Chem Lett 21(4):1206–1213. https://doi.org/10.1016/j.bmcl.2010.12.089
Bijsmans ITGW, Guercini C, Ramos Pittol JM et al (2015) The glucocorticoid mometasone furoate is a novel FXR ligand that decreases inflammatory but not metabolic gene expression. Sci Rep 5:14086. https://doi.org/10.1038/srep14086
Brzozowski AM, Pike ACW, Dauter Z et al (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389(6652):753–758. https://doi.org/10.1038/39645
Burris TP (2004) The hypolipidemic natural product guggulsterone is a promiscuous steroid receptor ligand. Mol Pharmacol 67(3):948–954. https://doi.org/10.1124/mol.104.007054
Carino A, Cipriani S, Marchianò S et al (2017) BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis. Sci Rep 7:42801. https://doi.org/10.1038/srep42801
Carino A, Biagioli M, Marchianò S et al (2018) Disruption of TFGβ-SMAD3 pathway by the nuclear receptor SHP mediates the antifibrotic activities of BAR704, a novel highly selective FXR ligand. Pharmacol Res 131:17–31. https://doi.org/10.1016/j.phrs.2018.02.033
Copeland RA (2016) The drug-target residence time model: a 10-year retrospective. Nat Rev Drug Discov 15(2):87–95
Cui J, Huang L, Zhao A et al (2003) Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump. J Biol Chem 278(12):10214–10220. https://doi.org/10.1074/jbc.M209323200
D’Amore C, Di Leva FS, Sepe V et al (2014) Design, synthesis, and biological evaluation of potent dual agonists of nuclear and membrane bile acid receptors. J Med Chem 57(3):937–954. https://doi.org/10.1021/jm401873d
Di Leva FS, Festa C, D’Amore C et al (2013) Binding mechanism of the farnesoid X receptor marine antagonist suvanine reveals a strategy to forestall drug modulation on nuclear receptors. Design, synthesis, and biological evaluation of novel ligands. J Med Chem 56(11):4701–4717. https://doi.org/10.1021/jm400419e
Di Leva FS, Festa C, Renga B et al (2015) Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism. Sci Rep 5:16605. https://doi.org/10.1038/srep16605
Di Leva FS, Festa C, Carino A et al (2019) Discovery of ((1, 2, 4-oxadiazol-5-yl)pyrrolidin-3-yl)ureidyl derivatives as selective nonsteroidal agonists of the G-protein coupled bile acid receptor-1. Sci Rep 9(1):2504. https://doi.org/10.1038/s41598-019-38840-z
Downes M, Verdecia MA, Roecker AJ et al (2003) A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol Cell 11(4):1079–1092. https://doi.org/10.1016/S1097-2765(03)00104-7
Duboc H, Taché Y, Hofmann AF (2014) The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis 46:302–312. https://doi.org/10.1016/j.dld.2013.10.021
Festa C, Renga B, D’Amore C et al (2014) Exploitation of cholane scaffold for the discovery of potent and selective farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 1 (GP-BAR1) ligands. J Med Chem 57(20):8477–8495. https://doi.org/10.1021/jm501273r
Festa C, De Marino S, Carino A et al (2017) Targeting bile acid receptors: discovery of a potent and selective farnesoid X receptor agonist as a new lead in the pharmacological approach to liver diseases. Front Pharmacol 8:162. https://doi.org/10.3389/fphar.2017.00162
Festa C, Finamore C, Marchianò S et al (2019) Investigation around the oxadiazole core in the discovery of a new chemotype of potent and selective FXR antagonists. ACS Med Chem Lett 10(4):504–510. https://doi.org/10.1021/acsmedchemlett.8b00534
Fiorucci S, Distrutti E (2015) Bile acid-activated receptors, intestinal microbiota, and the treatment of metabolic disorders. Trends Mol Med 21(11):702–714. https://doi.org/10.1016/j.molmed.2015.09.001
Flatt B, Martin R, Wang TL et al (2009) Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR). J Med Chem 52(4):904–907. https://doi.org/10.1021/jm8014124
Gertzen CGW, Spomer L, Smits SHJ et al (2015) Mutational mapping of the transmembrane binding site of the G-protein coupled receptor TGR5 and binding mode prediction of TGR5 agonists. Eur J Med Chem 104:57–72. https://doi.org/10.1016/j.ejmech.2015.09.024
Gilson MK, Zhou H-X (2007) Calculation of protein-ligand binding affinities. Annu Rev Biophys Biomol Struct 36:21–42. https://doi.org/10.1146/annurev.biophys.36.040306.132550
Gioiello A, MacChiarulo A, Carotti A et al (2011) Extending SAR of bile acids as FXR ligands: discovery of 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-amine. Bioorg Med Chem 19(8):2650–2658. https://doi.org/10.1016/j.bmc.2011.03.004
Gioiello A, Rosatelli E, Nuti R et al (2012) Patented TGR5 modulators: a review (2006–present). Expert Opin Ther Pat 22(12):1399–1414. https://doi.org/10.1517/13543776.2012.733000
Greife A, Felekyan S, Ma Q et al (2016) Structural assemblies of the di- and oligomeric G-protein coupled receptor TGR5 in live cells: an MFIS-FRET and integrative modelling study. Sci Rep 6:36792. https://doi.org/10.1038/srep36792
Guo C, Chen WD, Wang YD (2016) TGR5, not only a metabolic regulator. Front Physiol 7:646
Hofmann AF, Hagey LR, Krasowski MD (2010) Bile salts of vertebrates: structural variation and possible evolutionary significance. J Lipid Res 51(2):226–246. https://doi.org/10.1194/jlr.R000042
Jin L, Feng X, Rong H et al (2013) The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism. Nat Commun 4:1937. https://doi.org/10.1038/ncomms2924
Kawamata Y, Fujii R, Hosoya M et al (2003) A G protein-coupled receptor responsive to bile acids. J Biol Chem 278(11):9435–9440. https://doi.org/10.1074/jbc.M209706200
Kontoyianni M, McClellan LM, Sokol GS (2004) Evaluation of docking performance: comparative data on docking algorithms. J Med Chem 47(3):558–565. https://doi.org/10.1021/jm0302997
Li Y, Cheng KC, Niu CS et al (2017) Investigation of triamterene as an inhibitor of the TGR5 receptor: identification in cells and animals. Drug Des Devel Ther 11:1127–1134. https://doi.org/10.2147/DDDT.S131892
Limongelli V, Bonomi M, Parrinello M (2013) Funnel metadynamics as accurate binding free-energy method. Proc Natl Acad Sci 110(16):6358–6363. https://doi.org/10.1073/pnas.1303186110
Lu Y, Zheng W, Lin S et al (2018) Identification of an oleanane-type triterpene hedragonic acid as a novel farnesoid X receptor ligand with liver protective effects and anti-inflammatory activity. Mol Pharmacol 93(2):63–72. https://doi.org/10.1124/mol.117.109900
Lundquist JT IV, Harnish DC, Kim CY et al (2010) Improvement of physiochemical properties of the tetrahydroazepinoindole series of farnesoid X receptor (FXR) agonists: beneficial modulation of lipids in primates. J Med Chem 53(4):1774–1787. https://doi.org/10.1021/jm901650u
Macchiarulo A, Gioiello A, Thomas C et al (2013) Probing the binding site of bile acids in TGR5. ACS Med Chem Lett 4(12):1158–1162. https://doi.org/10.1021/ml400247k
Makishima M, Okamoto AY, Repa JJ et al (1999) Identification of a nuclear receptor for bile acids. Science 284(5418):1362–1365. https://doi.org/10.1126/science.284.5418.1362
Maloney PR, Parks DJ, Haffner CD et al (2000) Identification of a chemical tool for the orphan nuclear receptor FXR. J Med Chem 43(16):2971–2974
Massafra V, Pellicciari R, Gioiello A, van Mil SWC (2018) Progress and challenges of selective farnesoid X receptor modulation. Pharmacol Ther 191:162–177
Meyer U, Costantino G, Macchiarulo A, Pellicciari R (2005) Is antagonism of E/Z-guggulsterone at the farnesoid X receptor mediated by a noncanonical binding site? A molecular modeling study. J Med Chem 48:6948–6955. https://doi.org/10.1021/jm0505056
Mi LZ, Devarakonda S, Harp JM et al (2003) Structural basis for bile acid binding and activation of the nuclear receptor FXR. Mol Cell 11(4):1093–1100. https://doi.org/10.1016/S1097-2765(03)00112-6
Mustafi D, Palczewski K (2009) Topology of class A G protein-coupled receptors: insights gained from crystal structures of rhodopsins, adrenergic and adenosine receptors. Mol Pharmacol 75(1):1–12. https://doi.org/10.1124/mol.108.051938
Parks DJ, Blanchard SG, Bledsoe RK et al (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science 284(5418):1365–1368. https://doi.org/10.1126/science.284.5418.1365
Pellicciari R, Fiorucci S, Camaioni E et al (2002) 6α-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem 45(17):3569–3572. https://doi.org/10.1021/jm025529g
Pellicciari R, Gioiello A, Macchiarulo A et al (2009) Discovery of 6α-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity. J Med Chem 52(24):7958–7961. https://doi.org/10.1021/jm901390p
Pellicciari R, Passeri D, De Franco F et al (2016) Discovery of 3α,7α,11β-trihydroxy-6α-ethyl-5β-cholan-24-oic acid (TC-100), a novel bile acid as potent and highly selective FXR agonist for enterohepatic disorders. J Med Chem 59(19):9201–9214. https://doi.org/10.1021/acs.jmedchem.6b01126
Richter HGF, Benson GM, Blum D et al (2011) Discovery of novel and orally active FXR agonists for the potential treatment of dyslipidemia & diabetes. Bioorg Med Chem Lett 21(1):191–194. https://doi.org/10.1016/j.bmcl.2010.11.039
Rizzo G, Passeri D, De Franco F et al (2010) Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist. Mol Pharmacol 78(4):617–630. https://doi.org/10.1124/mol.110.064501
Sasaki T, Mita M, Ikari N et al (2017) Identification of key amino acid residues in the hTGR5-nomilin interaction and construction of its binding model. PLoS One 12(6):e0179226. https://doi.org/10.1371/journal.pone.0179226
Schneider G (2018) Automating drug discovery. Nat Rev Drug Discov 17(2):97–113
Schoch GA, D’Arcy B, Stihle M et al (2010) Molecular switch in the glucocorticoid receptor: active and passive antagonist conformations. J Mol Biol 395(3):568–577. https://doi.org/10.1016/j.jmb.2009.11.011
Sepe V, Renga B, Festa C et al (2014) Modification on ursodeoxycholic acid (UDCA) scaffold. Discovery of bile acid derivatives as selective agonists of cell-surface G-protein coupled bile acid receptor 1 (GP-BAR1). J Med Chem 57(18):7687–7701. https://doi.org/10.1021/jm500889f
Sepe V, Distrutti E, Limongelli V et al (2015) Steroidal scaffolds as FXR and GPBAR1 ligands: from chemistry to therapeutical application. Future Med Chem 7(9):1109–1135
Sepe V, Festa C, Renga B et al (2016a) Insights on FXR selective modulation. Speculation on bile acid chemical space in the discovery of potent and selective agonists. Sci Rep 6:19008. https://doi.org/10.1038/srep19008
Sepe V, Renga B, Festa C et al (2016b) Investigation on bile acid receptor regulators. Discovery of cholanoic acid derivatives with dual G-protein coupled bile acid receptor 1 (GPBAR1) antagonistic and farnesoid X receptor (FXR) modulatory activity. Steroids 105:59–67. https://doi.org/10.1016/j.steroids.2015.11.003
Sepe V, Marchianò S, Finamore C et al (2018) Novel isoxazole derivatives with potent fxr agonistic activity prevent acetaminophen-induced liver injury. ACS Med Chem Lett 10(4):407–412. https://doi.org/10.1021/acsmedchemlett.8b00423
Shiau AK, Barstad D, Radek JT et al (2002) Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism. Nat Struct Biol 9(5):359–364. https://doi.org/10.1038/nsb787
Sindhu T, Srinivasan P (2015a) Exploring the binding properties of agonists interacting with human TGR5 using structural modeling, molecular docking and dynamics simulations. RSC Adv 5(19):14202–14213. https://doi.org/10.1039/c4ra16617e
Sindhu T, Srinivasan P (2015b) Identification of potential dual agonists of FXR and TGR5 using e-pharmacophore based virtual screening. Mol Biosyst 11(5):1305–1318. https://doi.org/10.1039/c5mb00137d
Soisson SM, Parthasarathy G, Adams AD et al (2008) Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation. Proc Natl Acad Sci U S A 105(14):5337–5342. https://doi.org/10.1073/pnas.0710981105
Spomer L, Gertzen CGW, Schmitz B et al (2014) A membrane-proximal, C-terminal α-helix is required for plasma membrane localization and function of the G protein-coupled receptor (GPCR) TGR5. J Biol Chem 289(6):3689–3702. https://doi.org/10.1074/jbc.M113.502344
Teno N, Yamashita Y, Iguchi Y et al (2018) Nonacidic chemotype possessing N-acylated piperidine moiety as potent farnesoid X receptor (FXR) antagonists. ACS Med Chem Lett 9(2):78–83. https://doi.org/10.1021/acsmedchemlett.7b00363
Tiwari A, Maiti P (2009) TGR5: an emerging bile acid G-protein-coupled receptor target for the potential treatment of metabolic disorders. Drug Discov Today 14(9–10):523–530
Urizar NL, Liverman AB, Dodds DT et al (2002) A natural product that lowers cholesterol as an antagonist ligand for FXR. Science 296(5573):1703–1706. https://doi.org/10.1126/science.1072891
Williams S, Bledsoe RK, Collins JL et al (2003) X-ray crystal structure of the liver X receptor β ligand binding domain: regulation by a histidine-tryptophan switch. J Biol Chem 278(29):27138–27143. https://doi.org/10.1074/jbc.M302260200
Xu X, Xu X, Liu P et al (2015) Structural basis for small molecule NDB (N-benzyl-N-(3-(tertbutyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a selective antagonist of farnesoid X receptor α (FXRα) in stabilizing the homodimerization of the receptor. J Biol Chem 290(32):19888–19899. https://doi.org/10.1074/jbc.M114.630475
Yu DD, Sousa KM, Mattern DL et al (2015) Stereoselective synthesis, biological evaluation, and modeling of novel bile acid-derived G-protein coupled bile acid receptor 1 (GP-BAR1, TGR5) agonists. Bioorg Med Chem 23(7):1613–1628. https://doi.org/10.1016/j.bmc.2015.01.048
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Di Leva, F.S., Di Marino, D., Limongelli, V. (2019). Structural Insight into the Binding Mode of FXR and GPBAR1 Modulators. In: Fiorucci, S., Distrutti, E. (eds) Bile Acids and Their Receptors. Handbook of Experimental Pharmacology, vol 256. Springer, Cham. https://doi.org/10.1007/164_2019_234
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