The pregnane X receptor (PXR, NR1I2) is a xenobiotic-activated transcription factor with high levels of expression in the liver. It not only plays a key role in drug metabolism and elimination, but also promotes tumor growth, drug resistance, and metabolic diseases. It has been proposed as a therapeutic target for type II diabetes, metabolic syndrome, and inflammatory bowel disease, and PXR antagonists have recently been considered as a therapy for colon cancer. There are currently no PXR antagonists that can be used in a clinical setting. Nevertheless, due to the large and complex ligand-binding pocket (LBP) of the PXR, it is challenging to discover PXR antagonists at the orthosteric site. Alternative ligand binding sites of the PXR have also been proposed and are currently being studied. Recently, the AF-2 allosteric binding site of the PXR has been identified, with several compounds modulating the site discovered. Herein, we aimed to summarize our current knowledge of allosteric modulation of the PXR as well as our attempt to unlock novel allosteric sites. We describe the novel binding function 3 (BF-3) site of PXR, which is also common for other nuclear receptors. In addition, we also mention a novel allosteric site III based on in silico prediction. The identified allosteric sites of the PXR provide new insights into the development of safe and efficient allosteric modulators of the PXR receptor. We therefore propose that novel PXR allosteric sites might be promising targets for treating chronic metabolic diseases and some cancers.

Department of Pharmacology and Toxicology Faculty of Pharmacy Charles University Prague Heyrovskeho 1203 50005 Hradec Kralove Czech Republic

Department of Physical Chemistry and Biophysics Faculty of Pharmacy Charles University Prague Heyrovskeho 1203 50005 Hradec Kralove Czech Republic

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Moore D.D., Kato S., Xie W., Mangelsdorf D.J., Schmidt D.R., Xiao R., Kliewer S.A. International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor α, Farnesoid X Receptor β, Liver X Receptor α, Liver X Receptor β, and Vitamin D Receptor. Pharmacol. Rev. 2006;58:742–759. doi: 10.1124/pr.58.4.6. PubMed DOI

Smutny T., Mani S., Pavek P. Post-translational and Post-transcriptional Modifications of Pregnane X Receptor (PXR) in Regulation of the Cytochrome P450 Superfamily. Curr. Drug Metab. 2013;14:1059–1069. doi: 10.2174/1389200214666131211153307. PubMed DOI PMC

Jumper J., Evans R., Pritzel A., Green T., Figurnov M., Ronneberger O., Tunyasuvunakool K., Bates R., Žídek A., Potapenko A., et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596:583–589. doi: 10.1038/s41586-021-03819-2. PubMed DOI PMC

Perrakis A., Sixma T.K. AI revolutions in biology. EMBO Rep. 2021;22:e54046. doi: 10.15252/embr.202154046. PubMed DOI PMC

Monzon V., Haft D.H., Bateman A. Folding the unfoldable: Using AlphaFold to explore spurious proteins. Bioinform. Adv. 2022;2:vbab043. doi: 10.1093/bioadv/vbab043. PubMed DOI PMC

Hall A., Chanteux H., Menochet K., Ledecq M., Schulze M.E.D. Designing Out PXR Activity on Drug Discovery Projects: A Review of Structure-Based Methods, Empirical and Computational Approaches. J. Med. Chem. 2021;64:6413–6522. doi: 10.1021/acs.jmedchem.0c02245. PubMed DOI

Wallace B.D., Betts L., Talmage G., Pollet R.M., Holman N.S., Redinbo M.R. Structural and Functional Analysis of the Human Nuclear Xenobiotic Receptor PXR in Complex with RXRα. J. Mol. Biol. 2013;425:2561–2577. doi: 10.1016/j.jmb.2013.04.012. PubMed DOI PMC

Rigalli J.P., Theile D., Nilles J., Weiss J. Regulation of PXR Function by Coactivator and Corepressor Proteins: Ligand Binding Is Just the Beginning. Cells. 2021;10:3137. doi: 10.3390/cells10113137. PubMed DOI PMC

Bauer B., Hartz A.M.S., Fricker G., Miller D.S. Pregnane X Receptor Up-Regulation of P-Glycoprotein Expression and Transport Function at the Blood-Brain Barrier. Mol. Pharmacol. 2004;66:413–419. PubMed

Xing Y., Yan J., Niu Y. PXR: A center of transcriptional regulation in cancer. Acta Pharm. Sin. B. 2020;10:197–206. doi: 10.1016/j.apsb.2019.06.012. PubMed DOI PMC

Lehmann J.M., McKee D.D., Watson M.A., Willson T.M., Moore J.T., Kliewer S.A. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Investig. 1998;102:1016–1023. doi: 10.1172/JCI3703. PubMed DOI PMC

Kliewer S.A., Moore J.T., Wade L., Staudinger J.L., Watson M.A., Jones S.A., McKee D.D., Oliver B.B., Willson T.M., Zetterström R.H., et al. An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway. Cell. 1998;92:73–82. doi: 10.1016/S0092-8674(00)80900-9. PubMed DOI

Fukuen S., Fukuda T., Matsuda H., Sumida A., Yamamoto I., Inaba T., Azuma J. Identification of the novel splicing variants for the hPXR in human livers. Biochem. Biophys. Res. Commun. 2002;298:433–438. doi: 10.1016/S0006-291X(02)02469-5. PubMed DOI

Chan G.N.Y., Hoque M.T., Cummins C.L., Bendayan R. Regulation of P-glycoprotein by orphan nuclear receptors in human brain microvessel endothelial cells. J. Neurochem. 2011;118:163–175. doi: 10.1111/j.1471-4159.2011.07288.x. PubMed DOI

Atlas P. Nuclear Receptor Subfamily 1 Group I Member 2. [(accessed on 22 August 2022)]. Available online: https://www.proteinatlas.org/ENSG00000144852-NR1I2/tissue.

Nishimura M., Naito S., Yokoi T. Tissue-specific mRNA Expression Profiles of Human Nuclear Receptor Subfamilies. Drug Metab. Pharmacokinet. 2004;19:135–149. doi: 10.2133/dmpk.19.135. PubMed DOI

Oladimeji P.O., Chen T. PXR: More Than Just a Master Xenobiotic Receptor. Mol. Pharmacol. 2018;93:119–127. doi: 10.1124/mol.117.110155. PubMed DOI PMC

Creusot N., Gassiot M., Alaterre E., Chiavarina B., Grimaldi M., Boulahtouf A., Toporova L., Gerbal-Chaloin S., Daujat-Chavanieu M., Matheux A., et al. The Anti-Cancer Drug Dabrafenib Is a Potent Activator of the Human Pregnane X Receptor. Cells. 2020;9:1641. doi: 10.3390/cells9071641. PubMed DOI PMC

Feng F., Jiang Q., Cao S., Cao Y., Li R., Shen L., Zhu H., Wang T., Sun L., Liang E., et al. Pregnane X receptor mediates sorafenib resistance in advanced hepatocellular carcinoma. Biochim. Biophys. Acta (BBA)-Gen. Subj. 2018;1862:1017–1030. doi: 10.1016/j.bbagen.2018.01.011. PubMed DOI

Gwag T., Meng Z., Sui Y., Helsley R.N., Park S.H., Wang S., Greenberg R.N., Zhou C. Non-nucleoside reverse transcriptase inhibitor efavirenz activates PXR to induce hypercholesterolemia and hepatic steatosis. J. Hepatol. 2019;70:930–940. doi: 10.1016/j.jhep.2018.12.038. PubMed DOI PMC

Sinz M.W. Evaluation of pregnane X receptor (PXR)-mediated CYP3A4 drug-drug interactions in drug development. Drug Metab. Rev. 2013;45:3–14. doi: 10.3109/03602532.2012.743560. PubMed DOI

Shukla S.J., Sakamuru S., Huang R., Moeller T.A., Shinn P., VanLeer D., Auld D.S., Austin C.P., Xia M. Identification of Clinically Used Drugs That Activate Pregnane X Receptors. Drug Metab. Dispos. 2011;39:151–159. doi: 10.1124/dmd.110.035105. PubMed DOI PMC

Wang Y.-M., Ong S.S., Chai S.C., Chen T. Role of CAR and PXR in xenobiotic sensing and metabolism. Expert Opin. Drug Metab. Toxicol. 2012;8:803–817. doi: 10.1517/17425255.2012.685237. PubMed DOI PMC

Ma X., Shah Y.M., Guo G.L., Wang T., Krausz K.W., Idle J.R., Gonzalez F.J. Rifaximin Is a Gut-Specific Human Pregnane X Receptor Activator. J. Pharmacol. Exp. Ther. 2007;322:391–398. doi: 10.1124/jpet.107.121913. PubMed DOI

Daujat-Chavanieu M., Gerbal-Chaloin S. Regulation of CAR and PXR Expression in Health and Disease. Cells. 2020;9:2395. doi: 10.3390/cells9112395. PubMed DOI PMC

Pondugula S.R., Pavek P., Mani S. Pregnane X Receptor and Cancer: Context-Specificity is Key. Nucl. Recep. Res. 2016;3:101198. doi: 10.11131/2016/101198. PubMed DOI PMC

Bansard L., Bouvet O., Moutin E., Le Gall G., Giammona A., Pothin E., Bacou M., Hassen-Khodja C., Bordignon B., Bourgaux J.F., et al. Niclosamide induces miR-148a to inhibit PXR and sensitize colon cancer stem cells to chemotherapy. Stem Cell Rep. 2022;17:835–848. doi: 10.1016/j.stemcr.2022.02.005. PubMed DOI PMC

Wang H., Venkatesh M., Li H., Goetz R., Mukherjee S., Biswas A., Zhu L., Kaubisch A., Wang L., Pullman J., et al. Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice. J. Clin. Investig. 2011;121:3220–3232. doi: 10.1172/JCI41514. PubMed DOI PMC

Raynal C., Pascussi J.-M., Leguelinel G., Breuker C., Kantar J., Lallemant B., Poujol S., Bonnans C., Joubert D., Hollande F., et al. Pregnane × Receptor (PXR) expression in colorectal cancer cells restricts irinotecan chemosensitivity through enhanced SN-38 glucuronidation. Mol. Cancer. 2010;9:46. doi: 10.1186/1476-4598-9-46. PubMed DOI PMC

Planque C., Rajabi F., Grillet F., Finetti P., Bertucci F., Gironella M., Lozano J.J., Beucher B., Giraud J., Garambois V., et al. Pregnane X-receptor promotes stem cell-mediated colon cancer relapse. Oncotarget. 2016;7:56558–56573. doi: 10.18632/oncotarget.10646. PubMed DOI PMC

Niu X., Wu T., Li G., Gu X., Tian Y., Cui H. Insights into the critical role of the PXR in preventing carcinogenesis and chemotherapeutic drug resistance. Int. J. Biol. Sci. 2022;18:742–759. doi: 10.7150/ijbs.68724. PubMed DOI PMC

Lynch C., Sakamuru S., Huang R., Niebler J., Ferguson S.S., Xia M. Characterization of human pregnane X receptor activators identified from a screening of the Tox21 compound library. Biochem. Pharmacol. 2021;184:114368. doi: 10.1016/j.bcp.2020.114368. PubMed DOI PMC

Zhang J., Pavek P., Kamaraj R., Ren L., Zhang T. Dietary phytochemicals as modulators of human pregnane X receptor. Crit. Rev. Food Sci. Nutr. 2021:1–23. doi: 10.1080/10408398.2021.1995322. PubMed DOI

Karpale M., Hukkanen J., Hakkola J. Nuclear Receptor PXR in Drug-Induced Hypercholesterolemia. Cells. 2022;11:313. doi: 10.3390/cells11030313. PubMed DOI PMC

Sayaf K., Zanotto I., Russo F.P., Gabbia D., De Martin S. The Nuclear Receptor PXR in Chronic Liver Disease. Cells. 2021;11:61. doi: 10.3390/cells11010061. PubMed DOI PMC

Pondugula S.R., Mani S. Pregnane xenobiotic receptor in cancer pathogenesis and therapeutic response. Cancer Lett. 2013;328:1–9. doi: 10.1016/j.canlet.2012.08.030. PubMed DOI PMC

Chai S.C., Wright W.C., Chen T. Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer. Med. Res. Rev. 2020;40:1061–1083. doi: 10.1002/med.21648. PubMed DOI PMC

Biswas A., Mani S., Redinbo M.R., Krasowski M.D., Li H., Ekins S. Elucidating the ‘Jekyll and Hyde’ Nature of PXR: The Case for Discovering Antagonists or Allosteric Antagonists. Pharm. Res. 2009;26:1807–1815. doi: 10.1007/s11095-009-9901-7. PubMed DOI PMC

Li Y., Lin W., Wright W.C., Chai S.C., Wu J., Chen T. Building a Chemical Toolbox for Human Pregnane X Receptor Research: Discovery of Agonists, Inverse Agonists, and Antagonists Among Analogs Based on the Unique Chemical Scaffold of SPA70. J. Med. Chem. 2021;64:1733–1761. doi: 10.1021/acs.jmedchem.0c02201. PubMed DOI PMC

Watkins R.E., Wisely G.B., Moore L.B., Collins J.L., Lambert M.H., Williams S.P., Willson T.M., Kliewer S.A., Redinbo M.R. The human nuclear xenobiotic receptor PXR: Structural determinants of directed promiscuity. Science. 2001;292:2329–2333. doi: 10.1126/science.1060762. PubMed DOI

Lin W., Wang Y.M., Chai S.C., Lv L., Zheng J., Wu J., Zhang Q., Wang Y.D., Griffin P.R., Chen T. SPA70 is a potent antagonist of human pregnane X receptor. Nat. Commun. 2017;8:741. doi: 10.1038/s41467-017-00780-5. PubMed DOI PMC

Mustonen E.-K., Pantsar T., Rashidian A., Reiner J., Schwab M., Laufer S., Burk O. Target Hopping from Protein Kinases to PXR: Identification of Small-Molecule Protein Kinase Inhibitors as Selective Modulators of Pregnane X Receptor from TüKIC Library. Cells. 2022;11:1299. doi: 10.3390/cells11081299. PubMed DOI PMC

Ong S.S. Pregnane X Receptor in Drug Development. IntechOpen; London, UK: 2011. DOI

Motta S., Callea L., Giani Tagliabue S., Bonati L. Exploring the PXR ligand binding mechanism with advanced Molecular Dynamics methods. Sci. Rep. 2018;8:16207. doi: 10.1038/s41598-018-34373-z. PubMed DOI PMC

Huang P., Chandra V., Rastinejad F. Structural Overview of the Nuclear Receptor Superfamily: Insights into Physiology and Therapeutics. Annu. Rev. Physiol. 2010;72:247–272. doi: 10.1146/annurev-physiol-021909-135917. PubMed DOI PMC

Wu B., Li S., Dong D. 3D structures and ligand specificities of nuclear xenobiotic receptors CAR, PXR and VDR. Drug Discov. Today. 2013;18:574–581. doi: 10.1016/j.drudis.2013.01.001. PubMed DOI

Liu T., Beck J.P., Hao J. A concise review on hPXR ligand-recognizing residues and structure-based strategies to alleviate hPXR transactivation risk. RSC Med. Chem. 2022;13:129–137. doi: 10.1039/D1MD00348H. PubMed DOI PMC

Huber A.D., Wright W.C., Lin W., Majumder K., Low J.A., Wu J., Buchman C.D., Pintel D.J., Chen T. Mutation of a single amino acid of pregnane X receptor switches an antagonist to agonist by altering AF-2 helix positioning. Cell Mol. Life Sci. 2021;78:317–335. doi: 10.1007/s00018-020-03505-y. PubMed DOI PMC

Huber A.D., Li Y., Lin W., Galbraith A.N., Mishra A., Porter S.N., Wu J., Florke Gee R.R., Zhuang W., Pruett-Miller S.M., et al. SJPYT-195: A Designed Nuclear Receptor Degrader That Functions as a Molecular Glue Degrader of GSPT1. ACS Med. Chem. Lett. 2022;13:1311–1320. doi: 10.1021/acsmedchemlett.2c00223. PubMed DOI PMC

Zorba A., Nguyen C., Xu Y., Starr J., Borzilleri K., Smith J., Zhu H., Farley K.A., Ding W., Schiemer J., et al. Delineating the role of cooperativity in the design of potent PROTACs for BTK. Proc. Natl. Acad. Sci. USA. 2018;115:E7285–E7292. doi: 10.1073/pnas.1803662115. PubMed DOI PMC

Shimokawa K., Shibata N., Sameshima T., Miyamoto N., Ujikawa O., Nara H., Ohoka N., Hattori T., Cho N., Naito M. Targeting the Allosteric Site of Oncoprotein BCR-ABL as an Alternative Strategy for Effective Target Protein Degradation. ACS Med. Chem. Lett. 2017;8:1042–1047. doi: 10.1021/acsmedchemlett.7b00247. PubMed DOI PMC

Pettersen E.F., Goddard T.D., Huang C.C., Meng E.C., Couch G.S., Croll T.I., Morris J.H., Ferrin T.E. UCSF ChimeraX: Structure visualization for researchers, educators, and developers. Protein Sci. 2021;30:70–82. doi: 10.1002/pro.3943. PubMed DOI PMC

De Smet F., Christopoulos A., Carmeliet P. Allosteric targeting of receptor tyrosine kinases. Nat. Biotechnol. 2014;32:1113–1120. doi: 10.1038/nbt.3028. PubMed DOI

Gregory K.J., Sexton P.M., Christopoulos A. Overview of receptor allosterism. Curr. Protoc. Pharmacol. 2000;11:1–21. doi: 10.1002/0471141755.ph0121s51. PubMed DOI

Christopoulos A., Kenakin T. G protein-coupled receptor allosterism and complexing. Pharmacol. Rev. 2002;54:323–374. doi: 10.1124/pr.54.2.323. PubMed DOI

Smith N.J., Milligan G. Allostery at G Protein-Coupled Receptor Homo- and Heteromers: Uncharted Pharmacological Landscapes. Pharmacol. Rev. 2010;62:701–725. doi: 10.1124/pr.110.002667. PubMed DOI PMC

Conn P.J., Christopoulos A., Lindsley C.W. Allosteric modulators of GPCRs: A novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov. 2009;8:41–54. doi: 10.1038/nrd2760. PubMed DOI PMC

Christopoulos A. Advances in G Protein-Coupled Receptor Allostery: From Function to Structure. Mol. Pharmacol. 2014;86:463–478. doi: 10.1124/mol.114.094342. PubMed DOI

Lewis J.A., Scott S.A., Lavieri R., Buck J.R., Selvy P.E., Stoops S.L., Armstrong M.D., Brown H.A., Lindsley C.W. Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part I: Impact of alternative halogenated privileged structures for PLD1 specificity. Bioorg. Med. Chem. Lett. 2009;19:1916–1920. doi: 10.1016/j.bmcl.2009.02.057. PubMed DOI PMC

Cao A.M., Quast R.B., Fatemi F., Rondard P., Pin J.P., Margeat E. Allosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state. Nat. Commun. 2021;12:5426. doi: 10.1038/s41467-021-25620-5. PubMed DOI PMC

Reddy G.S., Kamaraj R., Hossain K.A., Kumar J.S., Thirupataiah B., Medishetti R., Sushma Sri N., Misra P., Pal M. Amberlyst-15 catalysed synthesis of novel indole derivatives under ultrasound irradiation: Their evaluation as serotonin 5-HT2C receptor agonists. Bioorg. Chem. 2021;116:105380. doi: 10.1016/j.bioorg.2021.105380. PubMed DOI

Burford N.T., Clark M.J., Wehrman T.S., Gerritz S.W., Banks M., O’Connell J., Traynor J.R., Alt A. Discovery of positive allosteric modulators and silent allosteric modulators of the mu-opioid receptor. Proc. Natl. Acad. Sci. USA. 2013;110:10830–10835. doi: 10.1073/pnas.1300393110. PubMed DOI PMC

Kenakin T., Strachan R.T. PAM-Antagonists: A Better Way to Block Pathological Receptor Signaling? Trends Pharmacol. Sci. 2018;39:748–765. doi: 10.1016/j.tips.2018.05.001. PubMed DOI

Fasciani I., Petragnano F., Aloisi G., Marampon F., Carli M., Scarselli M., Maggio R., Rossi M. Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics. Pharmaceuticals. 2020;13:388. doi: 10.3390/ph13110388. PubMed DOI PMC

Allosteric Database (ASD) Nuclear Hormone Receptor >> 202 Modulators. [(accessed on 14 May 2022)]. Available online: http://mdl.shsmu.edu.cn/ASD/module/modulators/modulators.jsp.

Changeux J.P., Christopoulos A. Allosteric Modulation as a Unifying Mechanism for Receptor Function and Regulation. Cell. 2016;166:1084–1102. doi: 10.1016/j.cell.2016.08.015. PubMed DOI

Moore T.W., Mayne C.G., Katzenellenbogen J.A. Minireview: Not Picking Pockets: Nuclear Receptor Alternate-Site Modulators (NRAMs) Mol. Endocrinol. 2010;24:683–695. doi: 10.1210/me.2009-0362. PubMed DOI PMC

Chen Y., Li J., Wu Z., Liu G., Li H., Tang Y., Li W. Computational Insight into the Allosteric Activation Mechanism of Farnesoid X Receptor. J. Chem. Inf. Model. 2020;60:1540–1550. doi: 10.1021/acs.jcim.9b00914. PubMed DOI

Gabler M., Kramer J., Schmidt J., Pollinger J., Weber J., Kaiser A., Lohr F., Proschak E., Schubert-Zsilavecz M., Merk D. Allosteric modulation of the farnesoid X receptor by a small molecule. Sci. Rep. 2018;8:6846. doi: 10.1038/s41598-018-25158-5. PubMed DOI PMC

Delfosse V., Dendele B., Huet T., Grimaldi M., Boulahtouf A., Gerbal-Chaloin S., Beucher B., Roecklin D., Muller C., Rahmani R., et al. Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds. Nat. Commun. 2015;6:8089. doi: 10.1038/ncomms9089. PubMed DOI PMC

Wang Y., Chirgadze N.Y., Briggs S.L., Khan S., Jensen E.V., Burris T.P. A second binding site for hydroxytamoxifen within the coactivator-binding groove of estrogen receptor β. Proc. Natl. Acad. Sci. USA. 2006;103:9908–9911. doi: 10.1073/pnas.0510596103. PubMed DOI PMC

Hughes T.S., Giri P.K., de Vera I.M., Marciano D.P., Kuruvilla D.S., Shin Y., Blayo A.L., Kamenecka T.M., Burris T.P., Griffin P.R., et al. An alternate binding site for PPARgamma ligands. Nat. Commun. 2014;5:3571. doi: 10.1038/ncomms4571. PubMed DOI PMC

Delfosse V., Huet T., Harrus D., Granell M., Bourguet M., Gardia-Parège C., Chiavarina B., Grimaldi M., Le Mével S., Blanc P., et al. Mechanistic insights into the synergistic activation of the RXR–PXR heterodimer by endocrine disruptor mixtures. Proc. Natl. Acad. Sci. USA. 2021;118:e2020551118. doi: 10.1073/pnas.2020551118. PubMed DOI PMC

Lane J.R., Sexton P.M., Christopoulos A. Bridging the gap: Bitopic ligands of G-protein-coupled receptors. Trends Pharmacol. Sci. 2013;34:59–66. doi: 10.1016/j.tips.2012.10.003. PubMed DOI

Zhang C., Wu J., Chen Q., Tan H., Huang F., Guo J., Zhang X., Yu H., Shi W. Allosteric binding on nuclear receptors: Insights on screening of non-competitive endocrine-disrupting chemicals. Environ. Int. 2022;159:107009. doi: 10.1016/j.envint.2021.107009. PubMed DOI

Pavek P. Pregnane X Receptor (PXR)-Mediated Gene Repression and Cross-Talk of PXR with Other Nuclear Receptors via Coactivator Interactions. Front. Pharmacol. 2016;7:456. doi: 10.3389/fphar.2016.00456. PubMed DOI PMC

La Sala G., Gunnarsson A., Edman K., Tyrchan C., Hogner A., Frolov A.I. Unraveling the Allosteric Cross-Talk between the Coactivator Peptide and the Ligand-Binding Site in the Glucocorticoid Receptor. J. Chem. Inf. Model. 2021;61:3667–3680. doi: 10.1021/acs.jcim.1c00323. PubMed DOI

Fischer A., Smieško M. Allosteric Binding Sites On Nuclear Receptors: Focus On Drug Efficacy and Selectivity. Int. J. Mol. Sci. 2020;21:534. doi: 10.3390/ijms21020534. PubMed DOI PMC

Wärnmark A., Treuter E., Wright A.P.H., Gustafsson J.-A.k. Activation Functions 1 and 2 of Nuclear Receptors: Molecular Strategies for Transcriptional Activation. Mol. Endocrinol. 2003;17:1901–1909. doi: 10.1210/me.2002-0384. PubMed DOI

Wang H., Huang H., Li H., Teotico D.G., Sinz M., Baker S.D., Staudinger J., Kalpana G., Redinbo M.R., Mani S. Activated pregnenolone X-receptor is a target for ketoconazole and its analogs. Clin. Cancer Res. 2007;13:2488–2495. doi: 10.1158/1078-0432.CCR-06-1592. PubMed DOI

Huang H., Wang H., Sinz M., Zoeckler M., Staudinger J., Redinbo M.R., Teotico D.G., Locker J., Kalpana G.V., Mani S. Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene. 2007;26:258–268. doi: 10.1038/sj.onc.1209788. PubMed DOI

Wang H., Li H., Moore L.B., Johnson M.D., Maglich J.M., Goodwin B., Ittoop O.R., Wisely B., Creech K., Parks D.J., et al. The phytoestrogen coumestrol is a naturally occurring antagonist of the human pregnane X receptor. Mol. Endocrinol. 2008;22:838–857. doi: 10.1210/me.2007-0218. PubMed DOI PMC

Ekins S., Kholodovych V., Ai N., Sinz M., Gal J., Gera L., Welsh W.J., Bachmann K., Mani S. Computational discovery of novel low micromolar human pregnane X receptor antagonists. Mol. Pharmacol. 2008;74:662–672. doi: 10.1124/mol.108.049437. PubMed DOI

Venkatesh M., Wang H., Cayer J., Leroux M., Salvail D., Das B., Wrobel J.E., Mani S. In vivo and in vitro characterization of a first-in-class novel azole analog that targets pregnane X receptor activation. Mol. Pharmacol. 2011;80:124–135. doi: 10.1124/mol.111.071787. PubMed DOI PMC

Ekins S., Chang C., Mani S., Krasowski M.D., Reschly E.J., Iyer M., Kholodovych V., Ai N., Welsh W.J., Sinz M., et al. Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites. Mol. Pharmacol. 2007;72:592–603. doi: 10.1124/mol.107.038398. PubMed DOI

Burk O., Kuzikov M., Kronenberger T., Jeske J., Keminer O., Thasler W.E., Schwab M., Wrenger C., Windshügel B. Identification of approved drugs as potent inhibitors of pregnane X receptor activation with differential receptor interaction profiles. Arch. Toxicol. 2018;92:1435–1451. doi: 10.1007/s00204-018-2165-4. PubMed DOI

Krausova L., Stejskalova L., Wang H., Vrzal R., Dvorak Z., Mani S., Pavek P. Metformin suppresses pregnane X receptor (PXR)-regulated transactivation of CYP3A4 gene. Biochem. Pharmacol. 2011;82:1771–1780. doi: 10.1016/j.bcp.2011.08.023. PubMed DOI PMC

Chen Y., Tang Y., Robbins G.T., Nie D. Camptothecin attenuates cytochrome P450 3A4 induction by blocking the activation of human pregnane X receptor. J. Pharmacol. Exp. Ther. 2010;334:999–1008. doi: 10.1124/jpet.110.168294. PubMed DOI PMC

Zhou C., Poulton E.J., Grun F., Bammler T.K., Blumberg B., Thummel K.E., Eaton D.L. The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor. Mol. Pharmacol. 2007;71:220–229. doi: 10.1124/mol.106.029264. PubMed DOI

Carazo A., Dusek J., Holas O., Skoda J., Hyrsova L., Smutny T., Soukup T., Dosedel M., Pávek P. Teriflunomide Is an Indirect Human Constitutive Androstane Receptor (CAR) Activator Interacting with Epidermal Growth Factor (EGF) Signaling. Front. Pharmacol. 2018;9:993. doi: 10.3389/fphar.2018.00993. PubMed DOI PMC

Kronenberger T., Keminer O., Wrenger C., Windshügel B. Drug Discovery and Development: From Molecules to Medicine. InTech; London, UK: 2015. Nuclear Receptor Modulators—Current Approaches and Future Perspectives. DOI

Abbott K.L., Chaudhury C.S., Chandran A., Vishveshwara S., Dvorak Z., Jiskrova E., Poulikova K., Vyhlidalova B., Mani S., Pondugula S.R. Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression. Mol. Pharmacol. 2019;95:324–334. doi: 10.1124/mol.118.114587. PubMed DOI PMC

Lack N.A., Axerio-Cilies P., Tavassoli P., Han F.Q., Chan K.H., Feau C., Leblanc E., Guns E.T., Guy R.K., Rennie P.S., et al. Targeting the Binding Function 3 (BF3) Site of the Human Androgen Receptor through Virtual Screening. J. Med. Chem. 2011;54:8563–8573. doi: 10.1021/jm201098n. PubMed DOI PMC

Slagsvold T., Kraus I., Bentzen T., Palvimo J., Saatcioglu F. Mutational Analysis of the Androgen Receptor AF-2 (Activation Function 2) Core Domain Reveals Functional and Mechanistic Differences of Conserved Residues Compared with Other Nuclear Receptors. Mol. Endocrinol. 2000;14:1603–1617. doi: 10.1210/mend.14.10.0544. PubMed DOI

Estebanez-Perpina E., Arnold L.A., Nguyen P., Rodrigues E.D., Mar E., Bateman R., Pallai P., Shokat K.M., Baxter J.D., Guy R.K., et al. A surface on the androgen receptor that allosterically regulates coactivator binding. Proc. Natl. Acad. Sci. USA. 2007;104:16074–16079. doi: 10.1073/pnas.0708036104. PubMed DOI PMC

Buzon V., Carbo L.R., Estruch S.B., Fletterick R.J., Estebanez-Perpina E. A conserved surface on the ligand binding domain of nuclear receptors for allosteric control. Mol. Cell Endocrinol. 2012;348:394–402. doi: 10.1016/j.mce.2011.08.012. PubMed DOI

Grosdidier S., Carbo L.R., Buzon V., Brooke G., Nguyen P., Baxter J.D., Bevan C., Webb P., Estebanez-Perpina E., Fernandez-Recio J. Allosteric conversation in the androgen receptor ligand-binding domain surfaces. Mol. Endocrinol. 2012;26:1078–1090. doi: 10.1210/me.2011-1281. PubMed DOI PMC

Kumar R., McEwan I.J. Nuclear Receptors: From Structure to the Clinic. 1st ed. Springer International Publishing; Cham, Switzerland: 2015. p. 1. DOI

Gallastegui N., Estébanez-Perpiñá E. Thinking Outside the Box: Alternative Binding Sites in the Ligand Binding Domain of Nuclear Receptors. In: McEwan I.J., Kumar R., editors. Nuclear Receptors: From Structure to the Clinic. Springer International Publishing; Cham, Switzerland: 2015. pp. 179–203. DOI

Jehle K., Cato L., Neeb A., Muhle-Goll C., Jung N., Smith E.W., Buzon V., Carbó L.R., Estébanez-Perpiñá E., Schmitz K., et al. Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-binding Motif. J. Biol. Chem. 2014;289:8839–8851. doi: 10.1074/jbc.M113.534859. PubMed DOI PMC

Xu X.J., Su J.G., Bizzarri A.R., Cannistraro S., Liu M., Zeng Y., Chen W.Z., Wang C.X. Detection of persistent organic pollutants binding modes with androgen receptor ligand binding domain by docking and molecular dynamics. BMC Struct. Biol. 2013;13:16. doi: 10.1186/1472-6807-13-16. PubMed DOI PMC

Hirte S., Burk O., Tahir A., Schwab M., Windshügel B., Kirchmair J. Development and Experimental Validation of Regularized Machine Learning Models Detecting New, Structurally Distinct Activators of PXR. Cells. 2022;11:1253. doi: 10.3390/cells11081253. PubMed DOI PMC

Huang W., Lu S., Huang Z., Liu X., Mou L., Luo Y., Zhao Y., Liu Y., Chen Z., Hou T., et al. Allosite: A method for predicting allosteric sites. Bioinformatics. 2013;29:2357–2359. doi: 10.1093/bioinformatics/btt399. PubMed DOI

Zha J., Li M., Kong R., Lu S., Zhang J. Explaining and Predicting Allostery with Allosteric Database and Modern Analytical Techniques. J. Mol. Biol. 2022;434:167481. doi: 10.1016/j.jmb.2022.167481. PubMed DOI

Gupta R., Srivastava D., Sahu M., Tiwari S., Ambasta R.K., Kumar P. Artificial intelligence to deep learning: Machine intelligence approach for drug discovery. Mol. Divers. 2021;25:1315–1360. doi: 10.1007/s11030-021-10217-3. PubMed DOI PMC

Huang M., Song K., Liu X., Lu S., Shen Q., Wang R., Gao J., Hong Y., Li Q., Ni D., et al. AlloFinder: A strategy for allosteric modulator discovery and allosterome analyses. Nucleic Acids Res. 2018;46:W451–W458. doi: 10.1093/nar/gky374. PubMed DOI PMC

Yang L., Li T., Li S., Wu Y., Shi X., Jin H., Liu Z., Zhao Y., Zhang L., Lee H.C., et al. Rational Design and Identification of Small-Molecule Allosteric Inhibitors of CD38. ChemBioChem. 2019;20:2485–2493. doi: 10.1002/cbic.201900169. PubMed DOI

Bonhaus D.W., Stefanich E., Loury D.N., Hsu S.A., Eglen R.M., Wong E.H. Allosteric interactions among agonists and antagonists at 5-hydroxytryptamine3 receptors. J. Neurochem. 1995;65:104–110. doi: 10.1046/j.1471-4159.1995.65010104.x. PubMed DOI

Saito M., Tsukuda M. Review of palonosetron: Emerging data distinguishing it as a novel 5-HT(3) receptor antagonist for chemotherapy-induced nausea and vomiting. Expert Opin. Pharmacother. 2010;11:1003–1014. doi: 10.1517/14656561003705746. PubMed DOI

Grundmann M., Bender E., Schamberger J., Eitner F. Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators. Int. J. Mol. Sci. 2021;22:1763. doi: 10.3390/ijms22041763. PubMed DOI PMC

Li L., Welch M.A., Li Z., Mackowiak B., Heyward S., Swaan P.W., Wang H. Mechanistic Insights of Phenobarbital-Mediated Activation of Human but Not Mouse Pregnane X Receptor. Mol. Pharmacol. 2019;96:345–354. doi: 10.1124/mol.119.116616. PubMed DOI PMC

Sinz M., Kim S., Zhu Z., Chen T., Anthony M., Dickinson K., Rodrigues A.D. Evaluation of 170 xenobiotics as transactivators of human pregnane X receptor (hPXR) and correlation to known CYP3A4 drug interactions. Curr. Drug Metab. 2006;7:375–388. doi: 10.2174/138920006776873535. PubMed DOI

Targeted Protein Degradation (TPD) for Immunotherapy: Understanding Proteolysis Targeting Chimera-Driven Ubiquitin-Proteasome Interactions