Target Information
| Target General Information | Top | |||||
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| Target ID |
T86273
(Former ID: TTDR01440)
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| Target Name |
G-protein coupled bile acid receptor 1 (GPBAR1)
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| Synonyms |
hGPCR19; hBG37; TGR5; Membrane-type receptor for bile acids; M-BAR; G-protein coupled receptor GPCR19; BG37
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| Gene Name |
GPBAR1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Type 2 diabetes mellitus [ICD-11: 5A11] | |||||
| Function |
Bile acid-binding induces its internalization, activation of extracellular signal-regulated kinase and intracellular cAMP production. May be involved in the suppression of macrophage functions by bile acids. Receptor for bile acid.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MTPNSTGEVPSPIPKGALGLSLALASLIITANLLLALGIAWDRRLRSPPAGCFFLSLLLA
GLLTGLALPTLPGLWNQSRRGYWSCLLVYLAPNFSFLSLLANLLLVHGERYMAVLRPLQP PGSIRLALLLTWAGPLLFASLPALGWNHWTPGANCSSQAIFPAPYLYLEVYGLLLPAVGA AAFLSVRVLATAHRQLQDICRLERAVCRDEPSALARALTWRQARAQAGAMLLFGLCWGPY VATLLLSVLAYEQRPPLGPGTLLSLLSLGSASAAAVPVAMGLGDQRYTAPWRAAAQRCLQ GLWGRASRDSPGPSIAYHPSSQSSVDLDLN Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T74P7I | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Sodium taurocholate | Drug Info | Phase 1/2 | Type-2 diabetes | [1] | |
| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | XL475 | Drug Info | Preclinical | Type-2 diabetes | [3] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | Sodium taurocholate | Drug Info | [1] | |||
| Agonist | [+] 4 Agonist drugs | + | ||||
| 1 | PMID29649907-Compound-8 | Drug Info | [4] | |||
| 2 | PMID29649907-Compound-INT767 | Drug Info | [4] | |||
| 3 | XL475 | Drug Info | [3] | |||
| 4 | INT-777 | Drug Info | [6] | |||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | Bile acid | Drug Info | [5] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Cholesterol | Ligand Info | |||||
| Structure Description | Cryo-EM structure of the P395-bound GPBAR-Gs complex | PDB:7CFM | ||||
| Method | Electron microscopy | Resolution | 3.00 Å | Mutation | Yes | [7] |
| PDB Sequence |
LSLALASLII
29 TANLLLALGI39 AWDRRLRSPP49 AGCFFLSLLL59 AGLLTGLALP69 TLPGLWNQSR 79 RGYWSCLLVY89 LAPNFSFLSL99 LANLLLVHGE109 RYMAVLRPLQ119 PPGSIRLALL 129 LTWAGPLLFA139 SLPALGWNHW149 TPGANCSSQA159 IFPAPYLYLE169 VYGLLLPAVG 179 AAAFLSVRVL189 ATAHRQLQDI199 CRLERAVCRD209 EPSALARALT219 WRQARAQAGA 229 MLLFGLCWGP239 YVATLLLSVL249 AYEQRPPLGP259 GTLLSLLSLG269 SASAAAVPVA 279 MGLGDQRYTA289 PWR
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PHE53
4.819
ALA101
3.433
LEU104
3.705
LEU105
3.296
GLY108
3.801
GLU109
3.252
MET112
3.177
GLN119
4.823
PRO120
4.805
PRO121
3.664
ALA127
4.643
LEU130
3.569
THR131
3.883
PRO135
4.603
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: INT-777 | Ligand Info | |||||
| Structure Description | Cryo-EM structure of the INT-777-bound GPBAR-Gs complex | PDB:7CFN | ||||
| Method | Electron microscopy | Resolution | 3.00 Å | Mutation | Yes | [7] |
| PDB Sequence |
LGLSLALASL
27 IITANLLLAL37 GIAWDRRLRS47 PPAGCFFLSL57 LLAGLLTGLA67 LPTLPGLWNQ 77 SRRGYWSCLL87 VYLAPNFSFL97 SLLANLLLVH107 GERYMAVLRP117 LQPPGSIRLA 127 LLLTWAGPLL137 FASLPALGWN147 HWTPGANCSS157 QAIFPAPYLY167 LEVYGLLLPA 177 VGAAAFLSVR187 VLATAHRQLQ197 DICRLERAVC207 RDEPSALARA217 LTWRQARAQA 227 GAMLLFGLCW237 GPYVATLLLS247 VLAYEQRPPL257 GPGTLLSLLS267 LGSASAAAVP 277 VAMGLGDQRY287 TAPW
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PHE53
4.016
LEU71
3.959
LEU74
2.981
TRP75
3.799
TYR89
3.643
PRO92
4.042
ASN93
3.784
PHE96
3.820
LEU97
4.902
ALA101
3.858
LEU104
3.782
LEU105
3.156
GLY108
4.743
GLU109
3.692
MET112
3.257
PRO121
4.180
GLY122
3.976
ALA127
4.372
LEU130
3.246
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Similarity Proteins
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There is no similarity protein (E value < 0.005) for this target
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| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Class A/1 (Rhodopsin-like receptors) | |||||
| 2 | G alpha (s) signalling events | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | GPCR ligand binding | |||||
| 2 | GPCR downstream signaling | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Bile acids and sphingosine-1-phosphate receptor 2 in hepatic lipid metabolism.Acta Pharmaceutica Sinica B Volume 5, Issue 2, March 2015, Pages 151-157. | |||||
| REF 2 | Clinical pipeline report, company report or official report of Intercept. | |||||
| REF 3 | Clinical pipeline report, company report or official report of Exelixis (2011). | |||||
| REF 4 | Farnesoid X receptor modulators 2014-present: a patent review.Expert Opin Ther Pat. 2018 May;28(5):351-364. | |||||
| REF 5 | Synthesis and SAR of 2-aryl-3-aminomethylquinolines as agonists of the bile acid receptor TGR5. Bioorg Med Chem Lett. 2010 Oct 1;20(19):5718-21. | |||||
| REF 6 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 37). | |||||
| REF 7 | Structural basis of GPBAR activation and bile acid recognition. Nature. 2020 Nov;587(7834):499-504. | |||||
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