GPBAR1

Summary

GPBAR1 (G protein-coupled bile acid receptor 1, HGNC:19680) is a protein-coding gene on chromosome 2q35, encoding G-protein coupled bile acid receptor 1 (Q8TDU6). G protein-coupled receptor for bile acid.

This gene encodes a member of the G protein-coupled receptor (GPCR) superfamily. This enzyme functions as a cell surface receptor for bile acids. Treatment of cells expressing this GPCR with bile acids induces the production of intracellular cAMP, activation of a MAP kinase signaling pathway, and internalization of the receptor. The receptor is implicated in the suppression of macrophage functions and regulation of energy homeostasis by bile acids. Alternative splicing results in multiple transcript variants encoding the same protein.

Source: NCBI Gene 151306 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 129 total
• Druggable target: yes — 21 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_170699

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19680
Approved symbol	GPBAR1
Name	G protein-coupled bile acid receptor 1
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	BG37, GPCR, TGR5, M-BAR, GPCR19, GPR131, MGC40597
Ensembl gene	ENSG00000179921
Ensembl biotype	protein_coding
OMIM	610147
Entrez	151306

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000479077, ENST00000519574, ENST00000521462, ENST00000522678, ENST00000971011, ENST00000971012, ENST00000971013

RefSeq mRNA: 4 — MANE Select: NM_170699 NM_001077191, NM_001077194, NM_001321950, NM_170699

CCDS: CCDS46515

Canonical transcript exons

ENST00000519574 — 2 exons

Exon	Start	End
ENSE00002302882	218261015	218261216
ENSE00003849566	218262680	218263861

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 94.59.

FANTOM5 (CAGE): breadth broad, TPM avg 2.4141 / max 241.4425, expressed in 374 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25298	2.1313	360
25300	0.1696	51
25299	0.1132	40

Top tissues by expression

240 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.59	silver quality
monocyte	CL:0000576	93.55	gold quality
leukocyte	CL:0000738	93.46	gold quality
granulocyte	CL:0000094	93.28	gold quality
decidua	UBERON:0002450	90.32	gold quality
gall bladder	UBERON:0002110	86.27	gold quality
blood	UBERON:0000178	84.60	gold quality
omental fat pad	UBERON:0010414	81.63	gold quality
peritoneum	UBERON:0002358	81.56	gold quality
adipose tissue of abdominal region	UBERON:0007808	81.20	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.39	gold quality
adipose tissue	UBERON:0001013	79.86	gold quality
apex of heart	UBERON:0002098	74.21	gold quality
spleen	UBERON:0002106	73.06	gold quality
mucosa of stomach	UBERON:0001199	73.00	gold quality
right atrium auricular region	UBERON:0006631	72.79	gold quality
left coronary artery	UBERON:0001626	72.57	gold quality
cardiac atrium	UBERON:0002081	72.33	gold quality
coronary artery	UBERON:0001621	71.89	gold quality
body of stomach	UBERON:0001161	71.78	gold quality
placenta	UBERON:0001987	70.66	gold quality
right coronary artery	UBERON:0001625	69.38	gold quality
fundus of stomach	UBERON:0001160	69.27	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	69.16	gold quality
vermiform appendix	UBERON:0001154	68.82	gold quality
muscle layer of sigmoid colon	UBERON:0035805	68.43	gold quality
stomach	UBERON:0000945	68.34	gold quality
right adrenal gland cortex	UBERON:0035827	68.01	gold quality
bone marrow	UBERON:0002371	67.47	gold quality
smooth muscle tissue	UBERON:0001135	67.20	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.44

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting GPBAR1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-3151-3P	97.80	66.16	479
HSA-MIR-3139	96.68	66.77	652
HSA-MIR-28-5P	96.16	66.12	579
HSA-MIR-708-5P	96.16	66.12	576

Literature-anchored findings (GeneRIF, showing 40)

• Expression of BG37 was detected in various specific tissues, suggesting its physiological role. (PMID:12419312)
• TGR5 is implicated in the suppression of macrophage functions by bile acids (PMID:12524422)
• Combined blockade of both epidermal growth factor receptors and GPCRs may be a rational strategy to treat cancers, including head and neck squamous cell carcinoma that shows cross-talk between GPCR and EGFR signaling pathways. (PMID:17178880)
• These results suggest that in AGS cells, DC transactivates EGFR through M-BAR- and ADAM/HB-EGF-dependent mechanisms. (PMID:17214962)
• This is the first report on the expression of TGR5 in sinusoidal endothelial cells. Regulation of eNOS by TGR5 connects bile salts with hepatic hemodynamics. (PMID:17326144)
• TGR5 mediates chloride secretion via activation of CFTR. The presence of the receptor in both the plasma membrane and the recycling endosome indicate that TGR5 can be regulated by translocation. (PMID:19582812)
• Our data suggest that a common genetic variation within the GPBAR1 gene may not play a major role in the development of prediabetic phenotypes in our white population (PMID:19716570)
• TGR5 signaling pathway is critical in regulating intestinal glucagon-like peptide-1 secretion in CHO cells transiently transfected hTGR5 gene. (PMID:19723493)
• The TGR5 is localized in the primary cilium of human cholangiocytes and the receptor could play an important role in coupling biliary bile acid concentration and composition to ductular bile formation. (PMID:20623999)
• resequencing of TGR5 along with functional investigations of novel variants (PMID:20811628)
• The ability of the bile acid analogues obtained by chemical modification of ursodeoxycholic acid (UDCA) for TGR5 activation in HEK 293 cells is reported. (PMID:21212509)
• The current knowledge on BA receptors is reviewed, with a strong focus on the cell membrane receptor TGR5, which has emerged as a promising target for intervention in metabolic diseases. (PMID:21691102)
• The aim of the present study was to determine the localization and function of the receptor in biliary epithelial cells. (PMID:21691103)
• The TGR5 gene is localized at chromosome 2q35, close to a genetic variant associated with both primary sclerosing cholangitis and ulcerative colitis in recent genome-wide association studies. (PMID:21691110)
• TGR5 is a key factor in energy expenditure by regulating metabolism. (PMID:21754919)
• Data suggest that variation in bile acid receptor TGR5 may contribute to altered small bowel transit and colonic transit in lower functional gastrointestinal disorders. (PMID:21883702)
• These results indicate that bile acids induce the differentiation of IL-12 hypo-producing dendritic cells from monocytes via the TGR5-cAMP pathway. (PMID:22236403)
• the mechanisms of metabolic regulation by FXR and TGR5 (PMID:22550135)
• this study demonstrates that the TGR5 expressed in the pancreatic beta cells regulates insulin secretion and highlights the importance of ongoing therapeutic strategies targeting TGR5 in the control of glucose homeostasis. (PMID:23022524)
• TGR5 is overexpressed in most gastric intestinal-type adenocarcinomas, and moderate to strong TGR5 staining is associated with decreased patient survival in all gastric adenocarcinomas. (PMID:23238937)
• Human adipose tissue TGR5 expression is positively correlated to obesity and reduced during diet-induced weight loss. (PMID:23523790)
• TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn’s disease. (PMID:23566200)
• TGR5 agonism induces NO production via Akt activation and intracellular Ca(2+) increase in vascular endothelial cells, and this function inhibits monocyte adhesion in response to inflammatory stimuli. (PMID:23619297)
• DCA, taurolithocholic acid, and oleanolic acid did not stimulate TGR5 association with beta-arrestin 1/2 or G protein-coupled receptor kinase (GRK) 2/5/6, as determined by bioluminescence resonance energy transfer (PMID:23818521)
• Data suggest that TGR5 is expressed in 2 cell types of term placenta, macrophage/trophoblast; TGR5 expression is low in maternal cholestasis; TGR5 appears to trigger different responses to bile acid/progesterone metabolites depending on cell type. (PMID:23849932)
• the secondary structure of the TGR5 membrane-proximal C terminus is the determining factor for plasma membrane localization and responsiveness towards extracellular ligands. (PMID:24338481)
• Our findings strongly suggested the combination of serum TGR5 promoter methylation and AFP enhanced the diagnostic value of AFP alone in discriminating HCC from CHB patients. (PMID:24465162)
• GPBAR1 SNP is associated with symptoms and pathobiology in IBS-D and IBS-C. (PMID:25012842)
• Study demonstrates that highly lipophilic 3-epi-betulinic acid derivatives can be potent and selective TGR5 agonists with improved cellular efficacy. (PMID:25283506)
• Because elevated levels of circulatory LPS may contribute to the development of insulin resistance, the results from this study suggest that bile acids through the activation of TGR5 may have a role in the development of insulin resistance as well. (PMID:25418122)
• GPBAR1 plays a role in secondary bile acid induced vasodilation via reglation of cystathionine gamma-lyase. The GPBAR1/CSE pathway might contribute to endothelial dysfunction and hyperdynamic circulation in liver cirrhosis. (PMID:25934094)
• Collectively, these data suggest the involvement of TGR5 in PLD and that TGR5 targeting in cystic cholangiocytes may have therapeutic potential. (PMID:26045278)
• These findings identify TGR5 as a suppressor of gastric cancer cell proliferation and migration (PMID:26417930)
• TGR5 is a mediator of bile acid-induced cholangiocyte proliferation and protects cholangiocytes from apoptosis but may trigger proliferation and apoptosis resistance in malignantly transformed cholangiocytes, promoting cholangiocarcinoma. (PMID:26420419)
• this is the first report of bile acid derivatives able to antagonize GPBAR1 and and farnesoid X receptor (FXR) modulatory activity. (PMID:26607331)
• TGR5 activation induces mitochondrial biogenesis and prevents renal oxidative stress and lipid accumulation, establishing a role for TGR5 in inhibiting Kidney Disease in Obesity and Diabetes Mellitus. (PMID:27045028)
• The generated contour maps revealed the important structural insights for the activity of the compounds. The results obtained from this study could be helpful in the development of novel and more potent agonists of TGR5. (PMID:27267434)
• anti-inflammation therapy targeting Gpbar1/NF-kappaB pathway could be effective in suppressing bile acid-induced inflammation and alleviating Intrahepatic cholestasis of pregnancy-associated fetal disorders. (PMID:27402811)
• GPBAR1 is expressed in advanced gastric cancers and its expression correlates with markers of epithelial-mesenchymal transition (PMID:27409173)
• TGR5 functions as a tumor-suppressor in patients with ampullary adenocarcinoma and preoperative hyperbilirubinemia (PMID:27510297)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gpbar1	ENSMUSG00000064272
rattus_norvegicus	Gpbar1	ENSRNOG00000087111
caenorhabditis_elegans		WBGENE00011372
caenorhabditis_elegans		WBGENE00011381
caenorhabditis_elegans		WBGENE00018886

Protein

Protein identifiers

G-protein coupled bile acid receptor 1 — Q8TDU6 (reviewed: Q8TDU6)

Alternative names: G-protein coupled receptor GPCR19, Membrane-type receptor for bile acids, hBG37

All UniProt accessions (1): Q8TDU6

UniProt curated annotations — full annotation on UniProt →

Function. G protein-coupled receptor for bile acid. Bile acid-binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase. GPBAR1 is coupled to G(s) G proteins and mediates activation of adenylate cyclase activity. Activated by bile acids, such as lithocholate, deoxycholate, chenodeoxycholate and cholate, in descending order. Apart from their role in lipid dietary absorption and cholesterol catabolism, bile acids act as an important signaling molecule, involved in processes, such as energy expenditure or tissue inflammation. GPBAR1-mediated signaling promotes energy expenditure and adiposity reduction in brown adipose tissue by activating adenylate cyclase, leading to DIO2 activation. Involved in bile acid promoted GLP-1 secretion.

Subcellular location. Cell membrane.

Tissue specificity. Ubiquitously expressed. Expressed at higher level in spleen and placenta. Expressed at lower level in other tissues. In digestive tissues, it is expressed in stomach, duodenum, ileocecum, ileum, jejunum, ascending colon, transverse colon, descending colon, cecum and liver, but not in esophagus and rectum.

Similarity. Belongs to the G-protein coupled receptor 1 family.

RefSeq proteins (4): NP_001070659, NP_001070662, NP_001308879, NP_733800* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (58 total): mutagenesis site 17, helix 16, topological domain 8, transmembrane region 7, strand 3, glycosylation site 2, chain 1, region of interest 1, compositionally biased region 1, disulfide bond 1, turn 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9GYO	ELECTRON MICROSCOPY	2.5
7CFM	ELECTRON MICROSCOPY	3
7CFN	ELECTRON MICROSCOPY	3
7XTQ	ELECTRON MICROSCOPY	3.2
7BW0	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TDU6-F1	80.40	0.26

Antibody-complex structures (SAbDab): 5 — 7BW0, 7CFM, 7CFN, 7XTQ, 9GYO

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (1): 85–155

Glycosylation sites (2): 4, 76

Mutagenesis-validated functional residues (17):

Position	Phenotype
71	decreased activation in response to bile acid-binding.
74	decreased activation in response to bile acid-binding.
75	does not affect activation in response to bile acid-binding.
89	does not affect activation in response to bile acid-binding.
96	decreased activation in response to bile acid-binding.
97	decreased activation in response to bile acid-binding.
104	decreased g(s)-mediated signaling in response to bile acid-binding.
120	does not affect g(s)-mediated signaling in response to bile acid-binding.
121	does not affect g(s)-mediated signaling in response to bile acid-binding.
130	decreased g(s)-mediated signaling in response to bile acid-binding.
166	decreased g(s)-mediated signaling in response to bile acid-binding.
169	decreased g(s)-mediated signaling in response to bile acid-binding.
240	increased constitutive activity but strongly decreased g(s)-mediated signaling in response to bile acid-binding.
244	decreased g(s)-mediated signaling in response to bile acids with a hydroxyl group at position r1.
263	slightly decreased g(s)-mediated signaling in response to bile acids with a hydroxyl group at position r3.
266	decreased g(s)-mediated signaling in response to bile acids with a hydroxyl group at position r2.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 100 (showing top): GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_APICAL_JUNCTION_ASSEMBLY, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_RESPONSE_TO_LIPID, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, LYF1_01, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOBP_ENERGY_HOMEOSTASIS, GOBP_CELL_JUNCTION_ASSEMBLY

GO Biological Process (8): adenylate cyclase-activating G protein-coupled bile acid receptor signaling pathway (GO:0038184), positive regulation of ERK1 and ERK2 cascade (GO:0070374), energy homeostasis (GO:0097009), cellular response to bile acid (GO:1903413), positive regulation of cholangiocyte proliferation (GO:1904056), regulation of bicellular tight junction assembly (GO:2000810), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (3): G protein-coupled bile acid receptor activity (GO:0038182), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515)

GO Cellular Component (4): cytoplasm (GO:0005737), plasma membrane (GO:0005886), signaling receptor complex (GO:0043235), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
GPCR ligand binding	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor activity	2
cellular anatomical structure	2
cell surface receptor signaling pathway	1
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
G protein-coupled bile acid receptor activity	1
bile acid signaling pathway	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
multicellular organismal-level homeostasis	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
response to bile acid	1
positive regulation of epithelial cell proliferation	1
regulation of cholangiocyte proliferation	1
cholangiocyte proliferation	1
bicellular tight junction assembly	1
regulation of cell junction assembly	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
adenylate cyclase-activating G protein-coupled bile acid receptor signaling pathway	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
protein-containing complex	1

Protein interactions and networks

STRING

1636 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPBAR1	NR1H4	Q96RI1	992
GPBAR1	DIO2	Q92813	834
GPBAR1	XCR1	P46094	790
GPBAR1	CYP7A1	P22680	775
GPBAR1	GCG	P01275	772
GPBAR1	S1PR2	O95136	754
GPBAR1	INS	P01308	740
GPBAR1	GPR119	Q8TDV5	734
GPBAR1	SLC10A2	Q12908	732
GPBAR1	NR1I2	O75469	724
GPBAR1	FGF19	O95750	719
GPBAR1	PYY	P10082	717
GPBAR1	DIO1	P49895	715
GPBAR1	FFAR2	O15552	701
GPBAR1	NR0B2	Q15466	695

IntAct

16 interactions, top by confidence:

A	B	Type	Score
HSPA9	GPBAR1	psi-mi:“MI:0915”(physical association)	0.460
HSPA9	GPBAR1	psi-mi:“MI:0403”(colocalization)	0.460
RAMP2	GPBAR1	psi-mi:“MI:0915”(physical association)	0.400
GPBAR1	RAMP3	psi-mi:“MI:0915”(physical association)	0.400
GPBAR1	SLC33A1	psi-mi:“MI:0914”(association)	0.350
	GPBAR1	psi-mi:“MI:0915”(physical association)	0.000
GPBAR1		psi-mi:“MI:0915”(physical association)	0.000
GPBAR1	lexA	psi-mi:“MI:0915”(physical association)	0.000
GPBAR1	dtpA	psi-mi:“MI:0915”(physical association)	0.000
fklB	GPBAR1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (27): GPBAR1 (Affinity Capture-MS), AGPAT5 (Affinity Capture-MS), SLC33A1 (Affinity Capture-MS), TM9SF4 (Affinity Capture-MS), RARS2 (Affinity Capture-MS), CMTM6 (Affinity Capture-MS), GGCX (Affinity Capture-MS), CYP2S1 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), TMEM87A (Affinity Capture-MS), ACVR1B (Affinity Capture-MS), ATP1A3 (Affinity Capture-MS), RAB29 (Affinity Capture-MS), SEC63 (Affinity Capture-MS), SGPL1 (Affinity Capture-MS)

ESM2 similar proteins: A0A6I8PUB9, O00155, O00270, O08726, O14842, O43603, O60755, O88626, O88634, O88853, O88854, P0C5I1, P13945, P46092, P50406, Q15722, Q28524, Q3T181, Q3ZC80, Q5IS65, Q60483, Q6XKD3, Q76JU8, Q76JU9, Q76JV1, Q80UC6, Q862A8, Q862A9, Q8HYC3, Q8K3T4, Q8MJV2, Q8MJV3, Q8TDU6, Q8TDU9, Q920E0, Q924U0, Q95252, Q969F8, Q96G91, Q96P69

Diamond homologs: P97717, Q80SS6, Q80T02, Q862A8, Q862A9, Q8TDU6, P15823, P18841, P35368, Q684M3, Q91X56, Q9JKM5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

129 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	102
Likely benign	20
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

477 predictions. Top by Δscore:

Variant	Effect	Δscore
2:218259569:G:GT	donor_gain	0.9800
2:218259759:C:T	donor_gain	0.9800
2:218259573:GACT:G	donor_gain	0.9700
2:218259618:G:GT	donor_gain	0.9700
2:218262162:G:GT	donor_gain	0.9700
2:218259712:A:T	donor_gain	0.9600
2:218259585:G:GT	donor_gain	0.9500
2:218259833:GCCT:G	donor_gain	0.9500
2:218262117:G:GT	donor_gain	0.9500
2:218260180:GATAG:G	donor_gain	0.9300
2:218261107:TCAG:T	acceptor_gain	0.9300
2:218261108:CAGC:C	acceptor_gain	0.9300
2:218261109:AGC:A	acceptor_gain	0.9300
2:218259582:C:T	donor_gain	0.9100
2:218259841:G:GT	donor_gain	0.9100
2:218259581:G:GT	donor_gain	0.9000
2:218259758:G:GG	donor_gain	0.9000
2:218260182:TAGGT:T	donor_loss	0.9000
2:218260183:AGG:A	donor_loss	0.9000
2:218260185:G:GA	donor_loss	0.9000
2:218260186:T:G	donor_loss	0.9000
2:218260187:GAG:G	donor_loss	0.9000
2:218259757:A:AG	donor_gain	0.8900
2:218260185:G:GG	donor_gain	0.8900
2:218260188:AGTA:A	donor_loss	0.8900
2:218259636:G:GT	donor_gain	0.8800
2:218261212:GCCAT:G	donor_gain	0.8800
2:218259754:GCCA:G	donor_gain	0.8700
2:218260182:TAG:T	donor_gain	0.8600
2:218262163:A:T	donor_gain	0.8600

AlphaMissense

2070 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:218262890:A:C	S56R	0.990
2:218262892:C:A	S56R	0.990
2:218262892:C:G	S56R	0.990
2:218263538:A:C	S272R	0.985
2:218263540:T:A	S272R	0.985
2:218263540:T:G	S272R	0.985
2:218263030:C:A	N102K	0.966
2:218263030:C:G	N102K	0.966
2:218263142:A:C	S140R	0.964
2:218263144:T:A	S140R	0.964
2:218263144:T:G	S140R	0.964
2:218263532:A:C	S270R	0.962
2:218263534:T:A	S270R	0.962
2:218263534:T:G	S270R	0.962
2:218263118:T:A	W132R	0.953
2:218263118:T:C	W132R	0.953
2:218263433:T:A	W237R	0.951
2:218263433:T:C	W237R	0.951
2:218263436:G:A	G238R	0.947
2:218263436:G:C	G238R	0.947
2:218263160:T:A	W146R	0.946
2:218263160:T:C	W146R	0.946
2:218262820:C:A	N32K	0.940
2:218262820:C:G	N32K	0.940
2:218263430:T:C	C236R	0.934
2:218263206:T:G	F161C	0.927
2:218262891:G:T	S56I	0.926
2:218263421:T:C	F233L	0.925
2:218263423:C:A	F233L	0.925
2:218263423:C:G	F233L	0.925

dbSNP variants (sampled 300 via entrez): RS1000235956 (2:218259509 C>T), RS1000249021 (2:218259150 C>T), RS1000442478 (2:218261514 G>A,C,T), RS1000601545 (2:218260743 G>A), RS1002239900 (2:218262344 C>G), RS1002279106 (2:218258141 A>T), RS1002430778 (2:218263853 G>A), RS1003749626 (2:218258546 G>A,C), RS1004332754 (2:218257631 A>T), RS1004686440 (2:218257871 C>G,T), RS1005290190 (2:218259189 A>G), RS1005501380 (2:218261690 T>C), RS1005753990 (2:218258869 C>T), RS1006347425 (2:218260189 G>A), RS1007042574 (2:218262638 G>A)

Disease associations

OMIM: gene MIM:610147 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002379_2	Pyoderma gangrenosum in inflammatory bowel disease	5.000000e-06
GCST004131_76	Inflammatory bowel disease	2.000000e-07
GCST006979_90	Heel bone mineral density	2.000000e-09
GCST90002385_460	High light scatter reticulocyte count	1.000000e-24
GCST90002393_390	Monocyte count	2.000000e-23
GCST90002407_37	White blood cell count	5.000000e-14

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006835	pyoderma gangrenosum
EFO:0009270	heel bone mineral density
EFO:0007986	reticulocyte count
EFO:0005091	monocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5409 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

21 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 874,039 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL103	PROGESTERONE	4	162,141
CHEMBL131	PREDNISOLONE	4	140,604
CHEMBL135	ESTRADIOL	4	123,080
CHEMBL1551	URSODIOL	4	22,553
CHEMBL205596	CHOLIC ACID	4	76,195
CHEMBL240597	CHENODIOL	4	24,403
CHEMBL272427	TAURURSODIOL	4	4,753
CHEMBL386630	TESTOSTERONE	4	129,997
CHEMBL406393	DEOXYCHOLIC ACID	4	63,215
CHEMBL566315	OBETICHOLIC ACID	4	3,314
CHEMBL90593	PRASTERONE	4	23,422
CHEMBL1254990	NORUCHOLIC ACID	3	148
CHEMBL408701	TAUROLITHOCHOLIC ACID	3	1,133
CHEMBL411070	GLYCOCHOLIC ACID	3	13,273
CHEMBL169	URSOLIC ACID	2	20,825
CHEMBL27769	STANOLONE	2	34,222
CHEMBL3746388	TERN-101	2	475
CHEMBL412272	TAURODEOXYCHOLIC ACID	2	6,983
CHEMBL269277	BETULINIC ACID	1	20,430
CHEMBL272621	HYODEOXYCHOLIC_ACID	1	2,873
CHEMBL4303545	SB-756050	1

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Bile acid receptor

Most potent curated ligand interactions (12 total), top 12:

Ligand	Action	Affinity	Parameter
compound 15 [PMID: 25411721]	Agonist	9.42	pEC50
compound 77A [PMID: 37639383]	Agonist	8.7	pEC50
compound 11d [PMID: 34406006]	Agonist	8.17	pEC50
lithocholic acid	Full agonist	7.5	pEC50
XYT528B	Agonist	7.08	pEC50
deoxycholic acid	Full agonist	6.2	pEC50
INT-767	Agonist	6.2	pEC50
S-EMCA	Agonist	6.09	pEC50
betulinic acid	Full agonist	5.98	pEC50
oleanolic acid	Full agonist	5.65	pEC50
chenodeoxycholic acid	Full agonist	5.4	pEC50
cholic acid	Full agonist	5.0	pEC50

Binding affinities (BindingDB)

351 measured of 356 human assays (357 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[4-(4-Fluoro-2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-3-(2-oxa-6-aza-spiro[3.3]heptane-6-sulfonyl)-5-trifluoromethyl-benzamide	EC50	5 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(4-Fluoro-2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-2,6-bis-trifluoro methyl-isonicotinamide	EC50	6 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(2-Fluoro-6-methoxy-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide	EC50	8 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(2-Chloro-phenyl)-pyridin-3-yl]-N-(2-methoxy-ethyl)-3,5-bis-trifluoromethyl-benzamide	EC50	8 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(2-Cyclobutoxy-phenyl)-pyridin-3-yl]-3-methanesulfonyl-N-methyl-5-trifluoromethyl-benzamide	EC50	8 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-(2-Methoxy-[3,4′]bipyridinyl-3′-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide	EC50	9 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(2-Methoxy-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide	EC50	11 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(4-Fluoro-2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide	EC50	11 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(2-Cyclopropoxy-phenyl)-pyridin-3-yl]-3-methanesulfonyl-N-methyl-5-trifluoromethyl-benzamide	EC50	11 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-methyl-N-(4-phenyl-3-pyridinyl)-3,5-bis(trifluoromethyl)benzamide	EC50	11 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
3-Dimethylsulfamoyl-N-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-5-trifluoromethyl-benzamide	EC50	12 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
Methyl 2-(N-(4-(2-fluoro-6-methoxyphenyl)pyridin-3-yl)-2,6-bis(trifluoromethyl) isonicotinamido)acetate	EC50	13 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(2-Fluoro-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide	EC50	14 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(2,6-Difluoro-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide	EC50	14 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
{(2,6-Bis-trifluoromethyl-pyridine-4-carbonyl)-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-amino}-acetic acid methyl ester	EC50	14 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-Methyl-3-nitro-N-(4-o-tolylpyridin-3-yl)-5-(trifluoromethyl)benzamide	EC50	15 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
3-(1,1-Dioxo-thiomorpholine-4-sulfonyl)-N-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-5-trifluoromethyl-benzamide	EC50	15 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
2-[(2,6-difluorophenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxyphenyl)-N-methylimidazol-4-amine	EC50	15 nM	US-10323016: Imidazol- or 1,2,4-triazol-derivatives and their use
N-[4-(2-Fluoro-6-methoxy-phenyl)-pyridin-3-yl]-3-methanesulfonyl-N-methyl-5-trifluoromethyl-benzamide	EC50	17 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
3-Methanesulfonyl-N-[4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-5-trifluoromethyl-benzamide	EC50	17 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(4-Fluoro-2-methoxy-phenyl)-pyridin-3-yl]-N-(2,2,2-trifluoro-ethyl)-2,6-bis-trifluoromethyl-isonicotinamide	EC50	18 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
3-Bromo-N-[4-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyridin-3-yl]-N-methyl-5-trifluoromethyl-benzamide	EC50	18 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-Methyl-N-(4-o-tolyl-pyridin-3-yl)-2,6-bis-trifluoromethyl-isonicotinamide	EC50	19 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-(2,2-Difluoro-ethyl)-N-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-2,6-bis-trifluoromethyl-isonicotinamide	EC50	19 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
3-(Azetidine-1-sulfonyl)-N-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-5-trifluoromethyl-benzamide	EC50	19 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(4-Fluoro-2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-3-(morpholine-4-sulfonyl)-5-trifluoromethyl-benzamide	EC50	20 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(2-Chloro-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide	EC50	21 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-Methyl-N-(4-o-tolyl-pyridin-3-yl)-3,5-bis-trifluoromethyl-benzamide	EC50	22 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
3-Chloro-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-5-trifluoromethyl-benzamide	EC50	22 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(4,5-Difluoro-2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-2,6-bis-trifluoromethyl-isonicotinamide	EC50	22 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(2-Fluoro-5-methoxy-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide	EC50	23 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
Methyl 2-(N-(4-(2-fluorophenyl)pyridin-3-yl)-2,6-bis(trifluoromethyl)isonicotinamido)acetate	EC50	23 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(4-Fluoro-2-methoxy-phenyl)-pyridin-3-yl]-2-methoxy-N-methyl-6-trifluoromethyl-isonicotinamide	EC50	23 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
3-Chloro-5-cyclopropyl-N-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-benzamide	EC50	23 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(5-Fluoro-2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide	EC50	26 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
2-Chloro-N-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-6-trifluoromethyl-isonicotinamide	EC50	26 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
Methyl 2-(N-(2-methoxy-3,4′-bipyridin-3′-yl)-2,6-bis(trifluoromethyl)isonicotinamido)acetate	EC50	27 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(2-Fluoro-6-methoxy-phenyl)-pyridin-3-yl]-3-methanesulfonyl-N-(2-methoxy-ethyl)-5-trifluoromethyl-benzamide	EC50	27 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-Methyl-N-[4-(2-trifluoromethoxy-phenyl)-pyridin-3-yl]-3,5-bis-trifluoromethyl-benzamide	EC50	29 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
3-Dimethylsulfamoyl-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-5-trifluoromethyl-benzamide	EC50	29 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-Cyanomethyl-N-(4-o-tolyl-pyridin-3-yl)-3,5-bis-trifluoromethyl-benzamide	EC50	29 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-(5-Fluoro-2-methoxy-[3,4′]bipyridinyl-3′-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide	EC50	30 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
3-Methanesulfonyl-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-5-trifluoromethyl-benzamide	EC50	30 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-(2-Methoxy-[3,4′]bipyridinyl-3′-yl)-N-(2,2,2-trifluoro-ethyl)-2,6-bis-trifluoromethyl-isonicotinamide	EC50	30 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(4-Fluoro-2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-3-(oxetan-3-ylsulfanyl)-5-trifluoromethyl-benzamide	EC50	30 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(4-Fluoro-2-methoxy-phenyl)-pyridin-3-yl]-3-(2-methoxy-ethanesulfonyl)-N-methyl-5-trifluoromethyl-benzamide	EC50	31 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-Carbamoylmethyl-N-[4-(2-fluoro-6-methoxy-phenyl)-pyridin-3-yl]-2,6-bis-trifluoromethyl-isonicotinamide	EC50	33 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
3-Bromo-N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-5-trifluoromethyl-benzamide	EC50	34 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
3-Methanesulfonyl-N-methyl-N-[4-(2-trifluoromethoxy-phenyl)-pyridin-3-yl]-5-trifluoromethyl-benzamide	EC50	34 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists
N-[4-(4-Fluoro-2-methoxy-phenyl)-pyridin-3-yl]-3-methanesulfonyl-N-oxazol-2-ylmethyl-5-trifluoromethyl-benzamide	EC50	35 nM	US-10385022: 3-amino-pyridines as GPBAR1 agonists

ChEMBL bioactivities

1330 potent at pChembl≥5 of 1422 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.24	EC50	0.057	nM	CHEMBL3793436
9.64	EC50	0.23	nM	CHEMBL2181247
9.55	EC50	0.28	nM	CHEMBL3290717
9.52	EC50	0.3	nM	CHEMBL2336232
9.51	EC50	0.31	nM	CHEMBL2181229
9.48	EC50	0.33	nM	CHEMBL4779837
9.37	EC50	0.43	nM	CHEMBL5270816
9.35	EC50	0.45	nM	CHEMBL3290716
9.34	EC50	0.46	nM	CHEMBL2181227
9.22	EC50	0.6	nM	CHEMBL2181228
9.14	EC50	0.72	nM	CHEMBL2181230
9.14	EC50	0.72	nM	CHEMBL2181226
9.05	EC50	0.9	nM	CHEMBL4779084
9.00	EC50	1	nM	CHEMBL3234570
9.00	EC50	1	nM	CHEMBL5290871
9.00	EC50	1	nM	CHEMBL612138
9.00	EC50	1	nM	CHEMBL5566751
9.00	EC50	1	nM	CHEMBL5574543
8.98	EC50	1.05	nM	CHEMBL4743463
8.96	EC50	1.09	nM	CHEMBL4790044
8.92	EC50	1.2	nM	CHEMBL2336233
8.92	EC50	1.2	nM	CHEMBL2336231
8.85	EC50	1.4	nM	CHEMBL3290715
8.85	EC50	1.4	nM	CHEMBL5284434
8.83	EC50	1.48	nM	CHEMBL3794442
8.82	EC50	1.5	nM	CHEMBL2181239
8.82	EC50	1.5	nM	CHEMBL3290713
8.80	EC50	1.6	nM	CHEMBL2331649
8.80	EC50	1.6	nM	CHEMBL4126062
8.80	EC50	1.585	nM	CHEMBL5434983
8.77	EC50	1.7	nM	CHEMBL3290720
8.74	EC50	1.8	nM	CHEMBL2331604
8.72	EC50	1.9	nM	CHEMBL3132966
8.70	EC50	2	nM	CHEMBL2331653
8.70	EC50	2	nM	CHEMBL3234565
8.70	EC50	2	nM	CHEMBL5394911
8.70	EC50	2	nM	CHEMBL5434983
8.68	EC50	2.1	nM	CHEMBL3132965
8.68	EC50	2.1	nM	CHEMBL4776876
8.64	EC50	2.3	nM	CHEMBL2331648
8.64	EC50	2.3	nM	CHEMBL3286440
8.64	EC50	2.3	nM	CHEMBL3793012
8.64	EC50	2.3	nM	CHEMBL4127302
8.62	EC50	2.4	nM	CHEMBL2336234
8.60	EC50	2.5	nM	CHEMBL2331646
8.60	EC50	2.5	nM	CHEMBL5427760
8.57	EC50	2.7	nM	CHEMBL2331651
8.55	EC50	2.8	nM	CHEMBL2181240
8.55	EC50	2.8	nM	CHEMBL2331655
8.55	EC50	2.8	nM	CHEMBL2181239

PubChem BioAssay actives

977 with measured affinity, of 2172 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5-[2-(3,4-dimethoxyphenyl)propan-2-yl]-1-(4-fluorophenyl)-2-[2-(4-imidazol-1-ylphenoxy)ethylsulfanyl]imidazole	1293464: Agonist activity at human TGR5 expressed in CHO-K1 cells after 5 hrs by luciferase reporter gene assay	ec50	0.0001	uM
4-[[3,5-bis(trifluoromethyl)phenyl]methyl]-6-(2-fluorophenyl)-5H-pyrido[3,2-f][1,4]oxazepin-3-one	710117: Agonist activity at human TGR5 expressed in HEK293 cells incubated for 5.5 hrs by CRE-driven luciferase reporter gene assay	ec50	0.0002	uM
(4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)-[3-[(1R)-1-phenylethyl]imidazol-4-yl]methanone	1694292: Agonist activity at human TGR5 transfected in HEK293T cells assessed intracellular cAMP level by HTRF assay	ec50	0.0003	uM
(4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)-[4-(2,5-dichloro-4-methylphenoxy)-3-pyridinyl]methanone	710117: Agonist activity at human TGR5 expressed in HEK293 cells incubated for 5.5 hrs by CRE-driven luciferase reporter gene assay	ec50	0.0003	uM
5-(2,3-dichlorophenoxy)-1,3-dimethyl-N-propan-2-yl-N-(pyridin-3-ylmethyl)pyrazole-4-carboxamide	731007: Agonist activity at doxycycline-promoter regulated overexpressed human TGR5 receptor in CHO cells assessed as elevation of cAMP level by induced-cAMP assay	ec50	0.0003	uM
[4-[(6-chloro-3-methyl-1-benzofuran-5-yl)oxy]-3-pyridinyl]-(4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)methanone	1154277: Agonist activity at human TGR5 expressed in HEK293 cells co-expressing CRE after 5.5 hrs by luciferase reporter gene assay	ec50	0.0003	uM
[4-[(6-chloro-3-methyl-1,2-benzoxazol-5-yl)oxy]-3-pyridinyl]-(4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)methanone	1944028: Agonist activity at TGR5 in human HEK293 cells assessed as increase in cAMP production	ec50	0.0004	uM
(4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)-[4-[(3-methyl-1-benzofuran-5-yl)oxy]-3-pyridinyl]methanone	1154277: Agonist activity at human TGR5 expressed in HEK293 cells co-expressing CRE after 5.5 hrs by luciferase reporter gene assay	ec50	0.0004	uM
(4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)-[4-(2,4,5-trichlorophenoxy)-3-pyridinyl]methanone	710117: Agonist activity at human TGR5 expressed in HEK293 cells incubated for 5.5 hrs by CRE-driven luciferase reporter gene assay	ec50	0.0005	uM
3-[(2-chloro-6-fluorophenyl)methylsulfanyl]-5-(4-methylphenyl)-[1,3]thiazolo[2,3-c][1,2,4]triazole	1944028: Agonist activity at TGR5 in human HEK293 cells assessed as increase in cAMP production	ec50	0.0005	uM
(4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)-[4-(2,4,5-trimethylphenoxy)-3-pyridinyl]methanone	710117: Agonist activity at human TGR5 expressed in HEK293 cells incubated for 5.5 hrs by CRE-driven luciferase reporter gene assay	ec50	0.0006	uM
(4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)-[4-(2,5-dimethylphenoxy)-3-pyridinyl]methanone	710117: Agonist activity at human TGR5 expressed in HEK293 cells incubated for 5.5 hrs by CRE-driven luciferase reporter gene assay	ec50	0.0007	uM
(4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)-[4-(2,5-dichloro-4-ethylphenoxy)-3-pyridinyl]methanone	710117: Agonist activity at human TGR5 expressed in HEK293 cells incubated for 5.5 hrs by CRE-driven luciferase reporter gene assay	ec50	0.0007	uM
methyl 5-[[3-(4-cyclopropyl-2,3-dihydroquinoxaline-1-carbonyl)-4-pyridinyl]oxy]-1-benzofuran-3-carboxylate	1741060: Agonist activity at human TGR5 expressed in HEK293 cells assessed as CRE-driven luciferase reporter gene activity incubated for 5.5 hrs and measured by Steady Glow reagent based luminescence assay	ec50	0.0009	uM
N-(4-fluorophenyl)-N-methyl-3-[(1R)-1-phenylethyl]imidazole-4-carboxamide	1694292: Agonist activity at human TGR5 transfected in HEK293T cells assessed intracellular cAMP level by HTRF assay	ec50	0.0010	uM
(1R,5S)-3-[4-[(1R,3Z)-1-(2,4-difluorophenyl)-3-hydroxyimino-3-(2-methyl-4-pyridinyl)propyl]phenyl]bicyclo[3.1.0]hexane-6-carboxylic acid	1944020: Agonist activity at human TGR5 transfected in CHO cells assessed as increase in cAMP production	ec50	0.0010	uM
2-[[4-[4-[(1R,3Z)-3-hydroxyimino-1-(2-methylphenyl)-3-(2-methyl-4-pyridinyl)propyl]phenyl]cyclohexanecarbonyl]amino]ethanesulfonic acid	2108153: Agonist activity at human TGR5 by HTRF assay	ec50	0.0010	uM
N-(4-chlorophenyl)-3-(3-methoxyphenyl)-N,5-dimethyl-1,2-oxazole-4-carboxamide	2108143: Agonist activity at human TGR5	ec50	0.0010	uM
5-(2-chlorophenyl)-1-[2-(2,5-dichlorophenoxy)phenyl]imidazole	2108167: Agonist activity at TGR5 (unknown origin) expressed in HEK293T cells assessed as cAMP level incubated for 30 mins by TR-FRET assay	ec50	0.0010	uM
(3R)-N-[2-(4-cyanophenyl)ethyl]-1-[6-[4-(oxetan-3-yl)piperazin-1-yl]-2-(trifluoromethyl)pyrimidin-4-yl]piperidine-3-carboxamide	1125916: Agonist activity at human TGR5 expressed in Jurkat cells assessed as intracellular cAMP level after 1 hr by HTRF assay	ec50	0.0010	uM
[4-(2-fluorophenyl)piperazin-1-yl]-[3-[(1R)-1-phenylethyl]imidazol-4-yl]methanone	1694292: Agonist activity at human TGR5 transfected in HEK293T cells assessed intracellular cAMP level by HTRF assay	ec50	0.0011	uM
5-(2,3-dichlorophenoxy)-N-ethyl-1,3-dimethyl-N-(pyridin-3-ylmethyl)pyrazole-4-carboxamide	731007: Agonist activity at doxycycline-promoter regulated overexpressed human TGR5 receptor in CHO cells assessed as elevation of cAMP level by induced-cAMP assay	ec50	0.0012	uM
5-(2,3-dichlorophenoxy)-1,3-dimethyl-N-[(6-methyl-3-pyridinyl)methyl]-N-propan-2-ylpyrazole-4-carboxamide	731007: Agonist activity at doxycycline-promoter regulated overexpressed human TGR5 receptor in CHO cells assessed as elevation of cAMP level by induced-cAMP assay	ec50	0.0012	uM
[4-[(6-chloro-1-benzofuran-5-yl)oxy]-3-pyridinyl]-(4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)methanone	1154277: Agonist activity at human TGR5 expressed in HEK293 cells co-expressing CRE after 5.5 hrs by luciferase reporter gene assay	ec50	0.0014	uM
(5R)-5-[2-chloro-3,5-bis(trifluoromethyl)phenyl]-4-[[4-(2,6-difluorophenyl)-3-pyridinyl]methyl]-3-(furan-2-yl)-5H-1,2,4-oxadiazole	1944029: Agonist activity at human TGR5 expressed in human HEK293 cells measured after 5.5 hrs by steady-glo luciferase assay	ec50	0.0014	uM
(4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)-[4-(2,5-dichlorophenoxy)-3-pyridinyl]methanone	710117: Agonist activity at human TGR5 expressed in HEK293 cells incubated for 5.5 hrs by CRE-driven luciferase reporter gene assay	ec50	0.0015	uM
(4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)-[4-[(3-methyl-1,2-benzoxazol-5-yl)oxy]-3-pyridinyl]methanone	1154277: Agonist activity at human TGR5 expressed in HEK293 cells co-expressing CRE after 5.5 hrs by luciferase reporter gene assay	ec50	0.0015	uM
5-[2-(3,4-dimethoxyphenyl)propan-2-yl]-1-(4-fluorophenyl)-2-[2-[4-(2-methylimidazol-1-yl)phenoxy]ethylsulfanyl]imidazole	1293464: Agonist activity at human TGR5 expressed in CHO-K1 cells after 5 hrs by luciferase reporter gene assay	ec50	0.0015	uM
(2-methoxyphenyl)methyl (4S)-4-(6-chloro-3-pyridinyl)-6-methyl-2-oxo-1-[[(2R)-oxolan-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate	2013126: Agonist activity at human TGR5 receptor expressed in HEK293 cells cotransfected with pCMV tag4b-TGR5 assessed as activation of intracellular cAMP production incubated overnight by luciferase reporter gene assay	ec50	0.0016	uM
2-(ethylamino)-6-[3-[4-(trifluoromethylsulfanyl)phenyl]propanoyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-4-carboxamide	731387: Agonist activity at human TGR5 expressed in deoxycycline-induced Flp-In-CHO-TO cells assessed as increase in intracellular cAMP measured after 48 hrs by HTRF competitive immunoassay	ec50	0.0016	uM
2-[2-[(2-chloro-6-fluorophenyl)methoxy]ethylsulfanyl]-5-[2-(3,4-dimethoxyphenyl)propan-2-yl]-1-(4-fluorophenyl)imidazole	1495063: Agonist activity at human TGR5 expressed in CHOK1 cells after 5 hrs by luciferase reporter gene assay	ec50	0.0016	uM
ethyl 6-chloro-5-[[3-(4-cyclopropyl-2,3-dihydroquinoxaline-1-carbonyl)-4-pyridinyl]oxy]-1-benzofuran-3-carboxylate	1154277: Agonist activity at human TGR5 expressed in HEK293 cells co-expressing CRE after 5.5 hrs by luciferase reporter gene assay	ec50	0.0017	uM
5-(2,3-dichlorophenoxy)-1,3-dimethyl-N-propan-2-yl-N-(1,3-thiazol-5-ylmethyl)pyrazole-4-carboxamide	731007: Agonist activity at doxycycline-promoter regulated overexpressed human TGR5 receptor in CHO cells assessed as elevation of cAMP level by induced-cAMP assay	ec50	0.0018	uM
(2-methoxyphenyl)methyl 4-(6-chloro-3-pyridinyl)-6-methyl-2-oxo-1-(oxolan-2-ylmethyl)-3,4-dihydropyridine-5-carboxylate	2013126: Agonist activity at human TGR5 receptor expressed in HEK293 cells cotransfected with pCMV tag4b-TGR5 assessed as activation of intracellular cAMP production incubated overnight by luciferase reporter gene assay	ec50	0.0020	uM
2-ethyl-6-[3-[4-(trifluoromethoxy)phenyl]propanoyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-4-carboxamide	731387: Agonist activity at human TGR5 expressed in deoxycycline-induced Flp-In-CHO-TO cells assessed as increase in intracellular cAMP measured after 48 hrs by HTRF competitive immunoassay	ec50	0.0020	uM
(3R)-N-[2-(4-cyanophenyl)ethyl]-1-[4-(4-methylpiperazin-1-yl)-6-(trifluoromethyl)pyrimidin-2-yl]piperidine-3-carboxamide	1125916: Agonist activity at human TGR5 expressed in Jurkat cells assessed as intracellular cAMP level after 1 hr by HTRF assay	ec50	0.0020	uM
propyl 5-[[3-(4-cyclopropyl-2,3-dihydroquinoxaline-1-carbonyl)-4-pyridinyl]oxy]-1-benzofuran-3-carboxylate	1741060: Agonist activity at human TGR5 expressed in HEK293 cells assessed as CRE-driven luciferase reporter gene activity incubated for 5.5 hrs and measured by Steady Glow reagent based luminescence assay	ec50	0.0021	uM
4-[2-[5-[2-(3,4-dimethoxyphenyl)propan-2-yl]-1-(4-fluorophenyl)imidazol-2-yl]sulfanylethoxymethyl]benzonitrile	1495063: Agonist activity at human TGR5 expressed in CHOK1 cells after 5 hrs by luciferase reporter gene assay	ec50	0.0023	uM
2-(ethylamino)-6-[3-[4-(trifluoromethoxy)phenyl]propanoyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-4-carboxamide	731007: Agonist activity at doxycycline-promoter regulated overexpressed human TGR5 receptor in CHO cells assessed as elevation of cAMP level by induced-cAMP assay	ec50	0.0023	uM
4-[2-[5-[2-(3,4-dimethoxyphenyl)propan-2-yl]-1-(4-fluorophenyl)imidazol-2-yl]sulfanylethoxy]benzonitrile	1293464: Agonist activity at human TGR5 expressed in CHO-K1 cells after 5 hrs by luciferase reporter gene assay	ec50	0.0023	uM
1-[5-(4-cyclopropyl-2,3-dihydroquinoxaline-1-carbonyl)-2-hydroxyphenyl]ethanone	1154276: Agonist activity at human TGR5	ec50	0.0023	uM
N-butan-2-yl-5-(2,3-dichlorophenoxy)-1,3-dimethyl-N-(pyridin-3-ylmethyl)pyrazole-4-carboxamide	731007: Agonist activity at doxycycline-promoter regulated overexpressed human TGR5 receptor in CHO cells assessed as elevation of cAMP level by induced-cAMP assay	ec50	0.0024	uM
N-[2-[2-[2-[2-[2-[2-[[2-[4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-methyl-2-oxo-1,4-diazepan-1-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-3-[2,5-dichloro-4-[2-(4-cyclopropyl-2,3-dihydroquinoxaline-1-carbonyl)thiophen-3-yl]oxyphenyl]propanamide	1986572: Agonist activity at human TGR5 expressed in human HEK293 cells co-expressing CRE-driven luciferase reporter gene assessed as luciferase activity incubated for 5.5 hrs by Steady-Glo based luciferase assay	ec50	0.0025	uM
2-(ethylamino)-6-[3-(4-propan-2-ylphenyl)propanoyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-4-carboxamide	731387: Agonist activity at human TGR5 expressed in deoxycycline-induced Flp-In-CHO-TO cells assessed as increase in intracellular cAMP measured after 48 hrs by HTRF competitive immunoassay	ec50	0.0025	uM
6-[3-[4-(1,1-difluoroethyl)phenyl]propanoyl]-2-(ethylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-4-carboxamide	731387: Agonist activity at human TGR5 expressed in deoxycycline-induced Flp-In-CHO-TO cells assessed as increase in intracellular cAMP measured after 48 hrs by HTRF competitive immunoassay	ec50	0.0027	uM
ethyl 5-[[3-(4-cyclopropyl-2,3-dihydroquinoxaline-1-carbonyl)-4-pyridinyl]oxy]-1-benzofuran-3-carboxylate	1741060: Agonist activity at human TGR5 expressed in HEK293 cells assessed as CRE-driven luciferase reporter gene activity incubated for 5.5 hrs and measured by Steady Glow reagent based luminescence assay	ec50	0.0028	uM
N-[2-[2-[2-[2-[2-[2-[2-[[2-[4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-methyl-2-oxo-1,4-diazepan-1-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-3-[2,5-dichloro-4-[2-(4-cyclopropyl-2,3-dihydroquinoxaline-1-carbonyl)thiophen-3-yl]oxyphenyl]propanamide;hydrofluoride	1986572: Agonist activity at human TGR5 expressed in human HEK293 cells co-expressing CRE-driven luciferase reporter gene assessed as luciferase activity incubated for 5.5 hrs by Steady-Glo based luciferase assay	ec50	0.0028	uM
N-[2-[2-[2-[2-[2-[2-[2-[2-[[2-[4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-methyl-2-oxo-1,4-diazepan-1-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-3-[2,5-dichloro-4-[2-(4-cyclopropyl-2,3-dihydroquinoxaline-1-carbonyl)thiophen-3-yl]oxyphenyl]propanamide	1986572: Agonist activity at human TGR5 expressed in human HEK293 cells co-expressing CRE-driven luciferase reporter gene assessed as luciferase activity incubated for 5.5 hrs by Steady-Glo based luciferase assay	ec50	0.0028	uM
(4-cyclobutyl-2,3-dihydroquinoxalin-1-yl)-[4-(2,5-dichlorophenoxy)-3-pyridinyl]methanone	710117: Agonist activity at human TGR5 expressed in HEK293 cells incubated for 5.5 hrs by CRE-driven luciferase reporter gene assay	ec50	0.0028	uM
2-cyclopropyl-6-[3-[4-(trifluoromethoxy)phenyl]propanoyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-4-carboxamide	731387: Agonist activity at human TGR5 expressed in deoxycycline-induced Flp-In-CHO-TO cells assessed as increase in intracellular cAMP measured after 48 hrs by HTRF competitive immunoassay	ec50	0.0028	uM

CTD chemical–gene interactions

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Lithocholic Acid	increases expression, affects binding, increases activity, increases abundance	5
Chenodeoxycholic Acid	increases abundance, increases expression, affects binding, increases activity	3
6alpha-ethyl-23(S)-methylcholic acid	increases activity, affects binding	2
Deoxycholic Acid	affects binding, increases expression	2
Dexamethasone	increases expression, affects cotreatment	2
Valproic Acid	affects expression, increases methylation	2
Cholic Acid	increases activity, increases expression, affects binding	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	increases expression	1
bisphenol A	increases expression, affects cotreatment	1
ursodoxicoltaurine	decreases expression	1
(+)-JQ1 compound	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Cyclic AMP	affects binding, increases abundance, increases activity	1
Air Pollutants, Occupational	affects expression, increases abundance, increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Bile Acids and Salts	increases activity	1
Calcium	affects binding, increases abundance, increases activity	1
Cholestanols	affects binding, increases activity	1
Colforsin	increases activity, increases abundance, affects binding	1
Indomethacin	affects cotreatment, increases expression	1
Oleanolic Acid	affects binding, increases activity, increases abundance	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Ursodeoxycholic Acid	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Okadaic Acid	increases expression	1

ChEMBL screening assays

235 unique, capped per target: 174 functional, 55 binding, 3 admet, 3 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1040510	Functional	Agonist activity at TGR5 expressed in human U2-OS cells assessed as increase in MRE/CRE-driven gene expression by luciferase reporter gene assay	Discovery of 3-aryl-4-isoxazolecarboxamides as TGR5 receptor agonists. — J Med Chem
CHEMBL2410510	Binding	Agonist activity at recombinant human GPBAR1 expressed in CHO cells	Discovery and optimisation of 1-hydroxyimino-3,3-diphenylpropanes, a new class of orally active GPBAR1 (TGR5) agonists. — Bioorg Med Chem Lett
CHEMBL4032766	ADMET	Agonist activity at human TGR5	Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH). — J Med Chem

Cellosaurus cell lines

4 cell lines: 2 spontaneously immortalized cell line, 1 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C0TT	ACTOne TGR5	Transformed cell line	Female
CVCL_H441	CHO-K1/GPBAR1	Spontaneously immortalized cell line	Female
CVCL_KV26	cAMP Hunter CHO-K1 GPBAR1 Gs	Spontaneously immortalized cell line	Female
CVCL_LA38	PathHunter U2OS GPBAR1 beta-arrestin	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.