Target Information
Target General Information | Top | |||||
---|---|---|---|---|---|---|
Target ID |
T98933
(Former ID: TTDR01227)
|
|||||
Target Name |
Thyroid hormone receptor beta (THRB)
|
|||||
Synonyms |
c-erbA-beta; c-erbA-2; THR1; Nuclear receptor subfamily 1 group A member 2; NR1A2; ERBA2
Click to Show/Hide
|
|||||
Gene Name |
THRB
|
|||||
Target Type |
Successful target
|
[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Hyper-lipoproteinaemia [ICD-11: 5C80] | |||||
Function |
High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine. Nuclear hormone receptor that can act as a repressor or activator of transcription.
Click to Show/Hide
|
|||||
BioChemical Class |
Nuclear hormone receptor
|
|||||
UniProt ID | ||||||
Sequence |
MTPNSMTENGLTAWDKPKHCPDREHDWKLVGMSEACLHRKSHSERRSTLKNEQSSPHLIQ
TTWTSSIFHLDHDDVNDQSVSSAQTFQTEEKKCKGYIPSYLDKDELCVVCGDKATGYHYR CITCEGCKGFFRRTIQKNLHPSYSCKYEGKCVIDKVTRNQCQECRFKKCIYVGMATDLVL DDSKRLAKRKLIEENREKRRREELQKSIGHKPEPTDEEWELIKTVTEAHVATNAQGSHWK QKRKFLPEDIGQAPIVNAPEGGKVDLEAFSHFTKIITPAITRVVDFAKKLPMFCELPCED QIILLKGCCMEIMSLRAAVRYDPESETLTLNGEMAVTRGQLKNGGLGVVSDAIFDLGMSL SSFNLDDTEVALLQAVLLMSSDRPGLACVERIEKYQDSFLLAFEHYINYRKHHVTHFWPK LLMKVTDLRMIGACHASRFLHMKVECPTELFPPLFLEVFED Click to Show/Hide
|
|||||
3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T12PPL |
Drugs and Modes of Action | Top | |||||
---|---|---|---|---|---|---|
Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
1 | Dextrothyroxine Sodium | Drug Info | Approved | High blood cholesterol level | [2] | |
Clinical Trial Drug(s) | [+] 8 Clinical Trial Drugs | + | ||||
1 | BCT303 | Drug Info | Phase 2 | Hypothyroidism | [3] | |
2 | MB-07811 | Drug Info | Phase 2 | Hyperlipidaemia | [4] | |
3 | MGL-3196 | Drug Info | Phase 2 | Familial hypercholesterolemia | [5] | |
4 | VK-2809 | Drug Info | Phase 2 | Hypercholesterolaemia | [5] | |
5 | Axitirome | Drug Info | Phase 1 | Hyperlipidaemia | [6] | |
6 | VK-0214 | Drug Info | Phase 1 | X-linked Adrenoleukodystrophy | [7] | |
7 | ZYT-1 | Drug Info | Phase 1 | Lipid metabolism disorder | [8] | |
8 | tiratricol | Drug Info | Clinical trial | Wound healing | [9] | |
Mode of Action | [+] 3 Modes of Action | + | ||||
Modulator | [+] 5 Modulator drugs | + | ||||
1 | Dextrothyroxine Sodium | Drug Info | [1] | |||
2 | BCT303 | Drug Info | [10] | |||
3 | MB-07811 | Drug Info | [11] | |||
4 | Axitirome | Drug Info | [6] | |||
5 | ZYT-1 | Drug Info | [10] | |||
Agonist | [+] 5 Agonist drugs | + | ||||
1 | MGL-3196 | Drug Info | [12] | |||
2 | VK-2809 | Drug Info | [5] | |||
3 | VK-0214 | Drug Info | [13] | |||
4 | tiratricol | Drug Info | [14] | |||
5 | rT3 | Drug Info | [14] | |||
Inhibitor | [+] 25 Inhibitor drugs | + | ||||
1 | (3,5-Dibromo-4-butoxy-phenyl)-acetic acid | Drug Info | [15] | |||
2 | (3,5-Dibromo-4-hexyloxy-phenyl)-acetic acid | Drug Info | [15] | |||
3 | (3,5-Dibromo-4-pentyloxy-phenyl)-acetic acid | Drug Info | [15] | |||
4 | (4-hexylphenyl)(oxiran-2-yl)methanone | Drug Info | [16] | |||
5 | (E)-1-(4-heptylphenyl)but-2-en-1-one | Drug Info | [16] | |||
6 | (Z)-4-(4-hexylphenylamino)-4-oxobut-2-enoic acid | Drug Info | [16] | |||
7 | 1-(4-(Hexyloxy)phenyl)-3-morpholinopropan-1-one | Drug Info | [17] | |||
8 | 1-(4-heptylphenyl)prop-2-en-1-one | Drug Info | [16] | |||
9 | 1-(4-hexylphenyl)-3-(propylamino)propan-1-one | Drug Info | [16] | |||
10 | 1-(4-hexylphenyl)-3-morpholinopropan-1-one | Drug Info | [16] | |||
11 | 1-(4-HEXYLPHENYL)PROP-2-EN-1-ONE | Drug Info | [18] | |||
12 | 1-(4-octylphenyl)prop-2-en-1-one | Drug Info | [16] | |||
13 | 2-hexylphenyl acrylate | Drug Info | [16] | |||
14 | 3-(3,5-Dibromo-4-hexyloxy-phenyl)-propionic acid | Drug Info | [15] | |||
15 | 3-(4-(benzyloxy)-3,5-dibromophenyl)propanoic acid | Drug Info | [19] | |||
16 | 3-(dibutylamino)-1-(4-hexylphenyl)propan-1-one | Drug Info | [16] | |||
17 | 3-(dimethylamino)-1-(4-heptylphenyl)propan-1-one | Drug Info | [17] | |||
18 | 3-(dimethylamino)-1-(4-hexylphenyl)propan-1-one | Drug Info | [16] | |||
19 | 3-bromo-1-(4-hexylphenyl)propan-1-one | Drug Info | [16] | |||
20 | 4-(3-(Dimethylamino)propanoyl)-N-hexylbenzamide | Drug Info | [17] | |||
21 | 4-(4-hexylphenyl)-4-oxobut-2-enoic acid | Drug Info | [16] | |||
22 | 4-hexylphenyl propiolate | Drug Info | [16] | |||
23 | Cacodylate Ion | Drug Info | [20] | |||
24 | Detrothyronine | Drug Info | [21] | |||
25 | GC-24 | Drug Info | [20] |
Cell-based Target Expression Variations | Top | |||||
---|---|---|---|---|---|---|
Cell-based Target Expression Variations |
Drug Binding Sites of Target | Top | |||||
---|---|---|---|---|---|---|
Ligand Name: Levothyroxine | Ligand Info | |||||
Structure Description | Thyroxine-Thyroid Hormone Receptor Interactions | PDB:1Y0X | ||||
Method | X-ray diffraction | Resolution | 3.10 Å | Mutation | No | [22] |
PDB Sequence |
SHMEELQKSI
208 GHKPEPTDEE218 WELIKTVTEA228 HVATNAQGSH238 WKQKRKFLPE248 DIGVDLEAFS 270 HFTKIITPAI280 TRVVDFAKKL290 PMFCELPCED300 QIILLKGCCM310 EIMSLRAAVR 320 YDPESETLTL330 NGEMAVTRGQ340 LKNGGLGVVS350 DAIFDLGMSL360 SSFNLDDTEV 370 ALLQAVLLMS380 SDRPGLACVE390 RIEKYQDSFL400 LAFEHYINYR410 KHHVTHFWPK 420 LLMKVTDLRM430 IGACHASRFL440 HMKVECPTEL450 FPPLFLEVFE460 |
|||||
|
ASN233
4.827
PHE269
4.184
PHE272
3.217
ILE275
3.709
ILE276
3.646
ALA279
3.544
ARG282
2.861
MET310
3.654
MET313
3.117
SER314
3.985
ARG316
3.510
ALA317
3.836
ARG320
3.939
|
|||||
Ligand Name: Liothyronine | Ligand Info | |||||
Structure Description | Crystal Structure of T3-Bound Thyroid Hormone Receptor | PDB:3GWS | ||||
Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [23] |
PDB Sequence |
EELQKSIGHK
211 PEPTDEEWEL221 IKTVTEAHVA231 TNAQGSHWKQ241 KRKFLPEDIG251 VDLEAFSHFT 273 KIITPAITRV283 VDFAKKLPMF293 ELPCEDQIIL304 LKGCCMEIMS314 LRAAVRYDPE 324 SETLTLNGEM334 AVTRGQLKNG344 GLGVVSDAIF354 DLGMSLSSFN364 LDDTEVALLQ 374 AVLLMSSDRP384 GLAVERIEKY395 QDSFLLAFEH405 YINYRKHHVT415 HFWPKLLMKV 425 TDLRMIGAHA436 SRFLHMKVEC446 PTELFPPLFL456 EVFE
|
|||||
|
ASN233
4.813
ALA234
4.865
PHE269
4.159
PHE272
3.101
THR273
4.727
ILE275
3.859
ILE276
3.502
ALA279
3.534
ARG282
2.675
MET310
3.728
MET313
3.380
SER314
4.322
ARG316
3.516
ALA317
3.842
|
|||||
Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
Click to View More Binding Site Information of This Target with Different Ligands |
Different Human System Profiles of Target | Top |
---|---|
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 Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
|
There is no similarity protein (E value < 0.005) for this target
|
Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
|
KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
---|---|---|---|
Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
|
Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
Thyroid hormone signaling pathway | hsa04919 | Affiliated Target |
|
Class: Organismal Systems => Endocrine system | Pathway Hierarchy |
Degree | 7 | Degree centrality | 7.52E-04 | Betweenness centrality | 8.87E-06 |
---|---|---|---|---|---|
Closeness centrality | 2.22E-01 | Radiality | 1.39E+01 | Clustering coefficient | 5.24E-01 |
Neighborhood connectivity | 3.96E+01 | Topological coefficient | 2.35E-01 | Eccentricity | 11 |
Download | Click to Download the Full PPI Network of This Target | ||||
Chemical Structure based Activity Landscape of Target | Top |
---|---|
Drug Property Profile of Target | Top | |
---|---|---|
(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
|
||
(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
|
||
(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
|
||
"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 |
Co-Targets | Top | |||||
---|---|---|---|---|---|---|
Co-Targets |
Target Poor or Non Binders | Top | |||||
---|---|---|---|---|---|---|
Target Poor or Non Binders |
Target Regulators | Top | |||||
---|---|---|---|---|---|---|
Target-regulating microRNAs | ||||||
Target-interacting Proteins |
Target Affiliated Biological Pathways | Top | |||||
---|---|---|---|---|---|---|
KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
1 | Neuroactive ligand-receptor interaction | |||||
2 | Thyroid hormone signaling pathway | |||||
PID Pathway | [+] 1 PID Pathways | + | ||||
1 | RXR and RAR heterodimerization with other nuclear receptor | |||||
Reactome | [+] 1 Reactome Pathways | + | ||||
1 | Nuclear Receptor transcription pathway | |||||
WikiPathways | [+] 3 WikiPathways | + | ||||
1 | SIDS Susceptibility Pathways | |||||
2 | Hematopoietic Stem Cell Differentiation | |||||
3 | Nuclear Receptors |
Target-Related Models and Studies | Top | |||||
---|---|---|---|---|---|---|
Target Validation |
References | Top | |||||
---|---|---|---|---|---|---|
REF 1 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. | |||||
REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
REF 3 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800037654) | |||||
REF 4 | ClinicalTrials.gov (NCT00879112) Study of MB07811 in Subjects With Hypercholesterolemia. U.S. National Institutes of Health. | |||||
REF 5 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 6 | Bacterial biosensors for screening isoform-selective ligands for human thyroid receptors alpha-1 and beta-1. FEBS Open Bio. 2012; 2: 247-253. | |||||
REF 7 | ClinicalTrials.gov (NCT04973657) Phase 1b, Multi-center, Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the Safety, Tolerability, PD and PK of VK0214, in Subjects With the Adrenomyeloneuropathy Form (AMN) of X-linked Adrenoleukodystrophy (X-ALD). U.S.National Institutes of Health. | |||||
REF 8 | ClinicalTrials.gov (NCT01543269) A Clinical Study to Evaluate the Safety,Tolerability and PK of ZYT1, Following Oral Administration in Healthy Volunteers. U.S. National Institutes of Health. | |||||
REF 9 | 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. (Ligand id: 2637). | |||||
REF 10 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
REF 11 | 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: 589). | |||||
REF 12 | Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-beta agonist. Atherosclerosis. 2013 Oct;230(2):373-80. | |||||
REF 13 | Clinical pipeline report, company report or official report of Viking Therapeutics | |||||
REF 14 | Binding of 3,5,3'-triiodothyronine (T3) and its analogs to the in vitro translational products of c-erbA protooncogenes: differences in the affinity of the alpha- and beta-forms for the acetic acid analog and failure of the human testis and kidney alpha-2 products to bind T3. Mol Endocrinol. 1990 Feb;4(2):227-34. | |||||
REF 15 | Thyroid receptor ligands. 3. Design and synthesis of 3,5-dihalo-4-alkoxyphenylalkanoic acids as indirect antagonists of the thyroid hormone receptor. J Med Chem. 2005 May 5;48(9):3114-7. | |||||
REF 16 | Inhibitors of the interaction of a thyroid hormone receptor and coactivators: preliminary structure-activity relationships. J Med Chem. 2007 Nov 1;50(22):5269-80. | |||||
REF 17 | Improvement of pharmacological properties of irreversible thyroid receptor coactivator binding inhibitors. J Med Chem. 2009 Jul 9;52(13):3892-901. | |||||
REF 18 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
REF 19 | Thyroid receptor ligands. Part 7: Indirect antagonists of the thyroid hormone receptor with improved affinity. Bioorg Med Chem Lett. 2007 Apr 1;17(7):2018-21. | |||||
REF 20 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
REF 21 | Thyroid receptor ligands. Part 5: novel bicyclic agonist ligands selective for the thyroid hormone receptor beta. Bioorg Med Chem Lett. 2006 Mar 1;16(5):1240-4. | |||||
REF 22 | Thyroxine-thyroid hormone receptor interactions. J Biol Chem. 2004 Dec 31;279(53):55801-8. | |||||
REF 23 | Structural rearrangements in the thyroid hormone receptor hinge domain and their putative role in the receptor function. J Mol Biol. 2006 Jul 14;360(3):586-98. |
If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.