title: Identifying ligands at orphan GPCRs: current status using structure-based approaches.
abstract: GPCRs are the most successful pharmaceutical targets in history. Nevertheless, the pharmacology of many GPCRs remains inaccessible as their endogenous or exogenous modulators have not been discovered. Tools that explore the physiological functions and pharmacological potential of these 'orphan' GPCRs, whether they are endogenous and/or surrogate ligands, are therefore of paramount importance. Rates of receptor deorphanization determined by traditional reverse pharmacology methods have slowed, indicating a need for the development of more sophisticated and efficient ligand screening approaches. Here, we discuss the use of structure-based ligand discovery approaches to identify small molecule modulators for exploring the function of orphan GPCRs. These studies have been buoyed by the growing number of GPCR crystal structures solved in the past decade, providing a broad range of template structures for homology modelling of orphans. This review discusses the methods used to establish the appropriate signalling assays to test orphan receptor activity and provides current examples of structure-based methods used to identify ligands of orphan GPCRs. Linked Articles This article is part of a themed section on Molecular Pharmacology of G Protein-Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc.
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.|St. Vincent's Clinical School, University of New South Wales, Darlinghurst, NSW, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Ngo
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Kufareva
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.|St. Vincent's Clinical School, University of New South Wales, Darlinghurst, NSW, Australia.
authors.forename: James Lj
authors.initials: JLj
authors.lastname: Coleman
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.|St. Vincent's Clinical School, University of New South Wales, Darlinghurst, NSW, Australia.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Graham
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia. n.smith@victorchang.edu.au.|St. Vincent's Clinical School, University of New South Wales, Darlinghurst, NSW, Australia. n.smith@victorchang.edu.au.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Smith
mesh_terms: D000818:Animals; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled
references.citation: J Chem Inf Model. 2014 Jun 23;54(6):1553-7
references.pmid: 24826842
references.citation: Diabetes Obes Metab. 2015 Jul;17(7):675-81
references.pmid: 25787200
references.citation: Nature. 2014 Jul 31;511(7511):557-62
references.pmid: 25042998
references.citation: J Biol Chem. 2015 Aug 7;290(32):19489-95
references.pmid: 26100628
references.citation: Acta Pharmacol Sin. 2012 Mar;33(3):372-84
references.pmid: 22266728
references.citation: J Med Chem. 2011 Dec 8;54(23):8195-206
references.pmid: 22007643
references.citation: Pharmacol Rev. 2005 Jun;57(2):279-88
references.pmid: 15914470
references.citation: J Lipid Res. 2008 Apr;49(4):797-803
references.pmid: 18174606
references.citation: Science. 2015 Mar 6;347(6226):1117-22
references.pmid: 25612609
references.citation: Science. 2013 Sep 20;341(6152):1394-9
references.pmid: 24052307
references.citation: Annu Rev Pharmacol Toxicol. 2004;44:43-66
references.pmid: 14744238
references.citation: Biochim Biophys Acta. 2007 Jun;1770(6):890-901
references.pmid: 17363172
references.citation: Br J Pharmacol. 2013 Feb;168(3):554-75
references.pmid: 22994528
references.citation: Nature. 2013 May 16;497(7449):338-43
references.pmid: 23636324
references.citation: Bioorg Med Chem Lett. 2006 Apr 1;16(7):1840-5
references.pmid: 16439116
references.citation: Science. 2014 Apr 4;344(6179):58-64
references.pmid: 24603153
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6843-8
references.pmid: 19342484
references.citation: Neuropharmacology. 2006 Mar;50(4):512-20
references.pmid: 16378626
references.citation: ACS Med Chem Lett. 2011 Feb 28;2(4):303-6
references.pmid: 24900311
references.citation: J Chem Inf Model. 2012 Dec 21;52(12):3263-77
references.pmid: 23121495
references.citation: PLoS One. 2013 Aug 02;8(8):e70857
references.pmid: 23936473
references.citation: Nat Chem Biol. 2011 Sep 18;7(11):769-78
references.pmid: 21926995
references.citation: Lancet. 2012 Apr 14;379(9824):1403-11
references.pmid: 22374408
references.citation: J Chem Inf Model. 2013 Mar 25;53(3):521-6
references.pmid: 23461591
references.citation: Methods Mol Biol. 2012;857:231-57
references.pmid: 22323224
references.citation: PLoS One. 2013 Sep 12;8(9):e74680
references.pmid: 24069330
references.citation: Nature. 2013 Jul 25;499(7459):444-9
references.pmid: 23863937
references.citation: Nat Protoc. 2009;4(5):706-31
references.pmid: 19390528
references.citation: Nat Rev Drug Discov. 2009 Jun;8(6):455-63
references.pmid: 19461661
references.citation: Curr Chem Genomics. 2010 Dec 21;4:84-91
references.pmid: 21331312
references.citation: J Biomol Screen. 2013 Jun;18(5):599-609
references.pmid: 23396314
references.citation: ACS Chem Biol. 2013 May 17;8(5):1018-26
references.pmid: 23485065
references.citation: Structure. 2012 Jun 6;20(6):967-76
references.pmid: 22681902
references.citation: Yeast. 2000 Jan 15;16(1):11-22
references.pmid: 10620771
references.citation: Nature. 2013 Jul 25;499(7459):438-43
references.pmid: 23863939
references.citation: Biochemistry. 2011 Jun 28;50(25):5633-47
references.pmid: 21534610
references.citation: Trends Pharmacol Sci. 2014 May;35(5):247-55
references.pmid: 24690241
references.citation: Annu Rev Pharmacol Toxicol. 2012;52:179-97
references.pmid: 21942629
references.citation: J Med Chem. 2012 Mar 8;55(5):1904-9
references.pmid: 22250781
references.citation: J Med Chem. 2012 Jul 26;55(14):6582-94
references.pmid: 22716043
references.citation: J Biomol Screen. 2009 Aug;14(7):789-97
references.pmid: 19525486
references.citation: Philos Trans R Soc Lond B Biol Sci. 2014 Jul 17;369(1647):20130314
references.pmid: 24914147
references.citation: J Biol Chem. 2003 Mar 28;278(13):11312-9
references.pmid: 12496283
references.citation: EMBO J. 2006 Jul 12;25(13):3012-23
references.pmid: 16778767
references.citation: Annu Rev Pharmacol Toxicol. 2013;53:127-46
references.pmid: 23020293
references.citation: Nature. 2013 Feb 14;494(7436):185-94
references.pmid: 23407534
references.citation: Curr Pharm Des. 2009;15(35):4026-48
references.pmid: 20028320
references.citation: Diabetes Care. 2013 Feb;36(2):245-50
references.pmid: 23086138
references.citation: Curr Opin Struct Biol. 2008 Apr;18(2):178-84
references.pmid: 18302984
references.citation: Science. 2005 Apr 22;308(5721):512-7
references.pmid: 15845844
references.citation: Nature. 2011 Jul 19;477(7366):549-55
references.pmid: 21772288
references.citation: Br J Pharmacol. 2006 Jul;148(5):619-28
references.pmid: 16702987
references.citation: Mol Pharmacol. 2013 Dec;84(6):794-807
references.pmid: 24021214
references.citation: Biochem Biophys Res Commun. 1997 Oct 20;239(2):543-7
references.pmid: 9344866
references.citation: Genomics. 2006 Sep;88(3):263-73
references.pmid: 16753280
references.citation: J Med Chem. 2008 Feb 14;51(3):625-33
references.pmid: 18193825
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D1098-106
references.pmid: 24234439
references.citation: Pharmacol Rev. 2013 May 17;65(3):967-86
references.pmid: 23686350
references.citation: Br J Pharmacol. 2015 Dec;172(24):5744-869
references.pmid: 26650439
references.citation: Science. 2009 Feb 13;323(5916):946-51
references.pmid: 19213921
references.citation: Methods Mol Biol. 2015;1272:91-106
references.pmid: 25563179
references.citation: Nature. 2014 Sep 4;513(7516):124-7
references.pmid: 25043059
references.citation: J Mol Biol. 1970 Mar;48(3):443-53
references.pmid: 5420325
references.citation: Nat Struct Mol Biol. 2015 May;22(5):362-9
references.pmid: 25895059
references.citation: Drug Discov Today Technol. 2013 Sep;10(3):e395-401
references.pmid: 24050136
references.citation: J Biol Chem. 2011 Mar 25;286(12):10628-40
references.pmid: 21220428
references.citation: Methods Mol Biol. 2012;857:189-205
references.pmid: 22323222
references.citation: Nature. 2011 Jan 13;469(7329):175-80
references.pmid: 21228869
references.citation: Structure. 2011 Aug 10;19(8):1108-26
references.pmid: 21827947
references.citation: Trends Endocrinol Metab. 2013 Aug;24(8):398-407
references.pmid: 23631851
references.citation: Methods Mol Biol. 2009;575:249-79
references.pmid: 19727619
references.citation: J Comput Aided Mol Des. 2011 Aug;25(8):743-52
references.pmid: 21744154
references.citation: Int Rev Cytol. 2006;252:163-218
references.pmid: 16984818
references.citation: J Comput Aided Mol Des. 2013 Apr;27(4):305-19
references.pmid: 23625023
references.citation: J Chem Inf Model. 2015 Mar 23;55(3):550-63
references.pmid: 25625646
references.citation: Methods Mol Biol. 2009;552:213-29
references.pmid: 19513652
references.citation: J Cell Sci. 2002 Feb 1;115(Pt 3):455-65
references.pmid: 11861753
references.citation: J Biol Chem. 2011 Jan 21;286(3):2101-10
references.pmid: 21097509
references.citation: Mol Pharmacol. 2003 Dec;64(6):1271-6
references.pmid: 14645655
references.citation: J Biol Chem. 2003 Mar 28;278(13):11303-11
references.pmid: 12496284
references.citation: Br J Pharmacol. 2015 Dec;172(24):6024-109
references.pmid: 26650445
references.citation: Methods Enzymol. 2013;522:263-78
references.pmid: 23374190
references.citation: Structure. 2014 Aug 5;22(8):1140-1151
references.pmid: 25043551
references.citation: J Chem Inf Model. 2013 Mar 25;53(3):638-48
references.pmid: 23398329
references.citation: ChemMedChem. 2014 Feb;9(2):256-75
references.pmid: 24353016
references.citation: J Biol Chem. 2012 Feb 3;287(6):3630-41
references.pmid: 22117076
references.citation: Structure. 2014 Aug 5;22(8):1120-1139
references.pmid: 25066135
references.citation: Nature. 2015 Nov 26;527(7579):477-83
references.pmid: 26550826
references.citation: Mol Inform. 2013 Feb;32(2):213-29
references.pmid: 27481282
references.citation: J Chem Inf Model. 2008 Jul;48(7):1396-410
references.pmid: 18570371
references.citation: PLoS One. 2013;8(2):e56742
references.pmid: 23468878
references.citation: J Chem Inf Model. 2014 Jun 23;54(6):1661-8
references.pmid: 24813470
references.citation: Br J Pharmacol. 2016 Oct;173(20):2934-51
references.pmid: 26837045
references.citation: J Med Chem. 2007 Jun 28;50(13):2981-9
references.pmid: 17552505
references.citation: Drug Discov Today. 2000 Jul;5(7):286-293
references.pmid: 10856911
references.citation: Mol Pharmacol. 2003 Jun;63(6):1256-72
references.pmid: 12761335
references.citation: PLoS One. 2013;8(1):e53347
references.pmid: 23335960
references.citation: J Chem Inf Model. 2007 Mar-Apr;47(2):488-508
references.pmid: 17288412
references.citation: J Med Chem. 2011 Mar 10;54(5):1365-78
references.pmid: 21319751
references.citation: Proteins. 2010 Jan;78(1):197-211
references.pmid: 20063437
references.citation: J Biol Chem. 2009 May 1;284(18):12328-38
references.pmid: 19286662
references.citation: J Biomol Screen. 2013 Oct;18(9):947-66
references.pmid: 23945874
references.citation: Nature. 2011 May 18;474(7352):521-5
references.pmid: 21593763
references.citation: J Biol Chem. 2011 Dec 9;286(49):41912-41916
references.pmid: 22025619
references.citation: Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5517-22
references.pmid: 22431600
references.citation: J Med Chem. 2010 Feb 25;53(4):1799-809
references.pmid: 20095623
references.citation: Nat Rev Drug Discov. 2012 Jan 03;11(1):12-3
references.pmid: 22212669
references.citation: J Med Chem. 2008 Jun 12;51(11):3145-53
references.pmid: 18459760
references.citation: Pharmacol Rev. 2010 Dec;62(4):701-25
references.pmid: 21079041
references.citation: BMC Bioinformatics. 2011 May 23;12:185
references.pmid: 21605354
references.citation: J Biol Chem. 2006 Dec 8;281(49):37447-56
references.pmid: 17041250
references.citation: Methods Enzymol. 2013;522:279-336
references.pmid: 23374191
references.citation: Mol Pharmacol. 2012 Dec;82(6):1094-103
references.pmid: 22930711
references.citation: Proteins. 2003 May 15;51(3):423-33
references.pmid: 12696053
references.citation: Nucleic Acids Res. 2016 Jan 4;44(D1):D746-52
references.pmid: 26481351
references.citation: Drug Discov Today. 2015 Jul;20(7):784-9
references.pmid: 25462532
references.citation: Nat Rev Mol Cell Biol. 2015 Feb;16(2):69-81
references.pmid: 25589408
references.citation: Nature. 2003 Mar 13;422(6928):173-6
references.pmid: 12629551
references.citation: J Chem Inf Model. 2012 Oct 22;52(10):2705-14
references.pmid: 22947092
references.citation: Biochem J. 2010 Dec 15;432(3):451-9
references.pmid: 20919992
references.citation: J Pharmacol Exp Ther. 2008 Feb;324(2):463-74
references.pmid: 18006692
references.citation: Nat Rev Drug Discov. 2013 Aug;12(8):630-44
references.pmid: 23903222
references.citation: Pharmacol Rev. 2008 Dec;60(4):405-17
references.pmid: 19047536
references.citation: Mol Pharmacol. 2013 Oct;84(4):528-40
references.pmid: 23887926
references.citation: J Chem Theory Comput. 2008 May;4(5):835-846
references.pmid: 19119325
references.citation: J Biol Chem. 2007 Oct 5;282(40):29248-55
references.pmid: 17699519