Target Information
| Target General Information | Top | |||||
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| Target ID |
T77796
(Former ID: TTDR01197)
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| Target Name |
Thyrotropin-releasing hormone receptor (TRHR)
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| Synonyms |
Thyroliberin receptor; TRH-R
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| Gene Name |
TRHR
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Central nervous system disease [ICD-11: 8A04-8D87] | |||||
| Function |
Receptor for thyrotropin-releasing hormone. This receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MENETVSELNQTQLQPRAVVALEYQVVTILLVLIICGLGIVGNIMVVLVVMRTKHMRTPT
NCYLVSLAVADLMVLVAAGLPNITDSIYGSWVYGYVGCLCITYLQYLGINASSCSITAFT IERYIAICHPIKAQFLCTFSRAKKIIIFVWAFTSLYCMLWFFLLDLNISTYKDAIVISCG YKISRNYYSPIYLMDFGVFYVVPMILATVLYGFIARILFLNPIPSDPKENSKTWKNDSTH QNTNLNVNTSNRCFNSTVSSRKQVTKMLAVVVILFALLWMPYRTLVVVNSFLSSPFQENW FLLFCRICIYLNSAINPVIYNLMSQKFRAAFRKLCNCKQKPTEKPANYSVALNYSVIKES DHFSTELDDITVTDTYLSATKVSFDDTCLASEVSFSQS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | protirelin | Drug Info | Approved | Central nervous system disease | [2] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | AZETIRELIN | Drug Info | Phase 3 | Pain | [3] | |
| Discontinued Drug(s) | [+] 3 Discontinued Drugs | + | ||||
| 1 | MONTIRELIN TETRAHYDRATE | Drug Info | Discontinued in Preregistration | Pain | [4] | |
| 2 | Posatirelin | Drug Info | Discontinued in Phase 3 | Neurodegenerative disorder | [5] | |
| 3 | JTP-2942 | Drug Info | Discontinued in Phase 2 | Cognitive impairment | [6] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Modulator | [+] 6 Modulator drugs | + | ||||
| 1 | protirelin | Drug Info | [1] | |||
| 2 | AZETIRELIN | Drug Info | [7], [8] | |||
| 3 | MONTIRELIN TETRAHYDRATE | Drug Info | [8], [9] | |||
| 4 | Posatirelin | Drug Info | [10] | |||
| 5 | JTP-2942 | Drug Info | [11] | |||
| 6 | MK-771 | Drug Info | [16] | |||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | C4X-101 | Drug Info | [12] | |||
| 2 | CORYMBONE B | Drug Info | [13] | |||
| Agonist | [+] 1 Agonist drugs | + | ||||
| 1 | MeTRH | Drug Info | [14], [15] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| 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 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 Pathway Affiliation
Biological Network Descriptors
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Calcium signaling pathway | hsa04020 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.07E-04 | Radiality | 3.98E-03 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.00E+00 | Topological coefficient | . | Eccentricity | 1 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| 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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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Calcium signaling pathway | |||||
| 2 | Neuroactive ligand-receptor interaction | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Thyrotropin-releasing hormone receptor signaling pathway | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Peptide ligand-binding receptors | |||||
| 2 | G alpha (q) signalling events | |||||
| WikiPathways | [+] 5 WikiPathways | + | ||||
| 1 | GPCRs, Class A Rhodopsin-like | |||||
| 2 | Gastrin-CREB signalling pathway via PKC and MAPK | |||||
| 3 | Peptide GPCRs | |||||
| 4 | GPCR ligand binding | |||||
| 5 | GPCR downstream signaling | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| Target QSAR Model | ||||||
| References | Top | |||||
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| REF 1 | Company report (takeda) | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 3 | Developing a metagenomic view of xenobiotic metabolism. Pharmacol Res. 2013 March; 69(1): 21-31. | |||||
| REF 4 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001824) | |||||
| REF 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005568) | |||||
| REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002435) | |||||
| REF 7 | Intestinal absorption of azetirelin, a new thyrotropin-releasing hormone (TRH) analogue. II. In situ and in vitro absorption characteristics of azetirelin from the rat intestine. Biol Pharm Bull. 1995 Jul;18(7):976-9. | |||||
| REF 8 | Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery. Nucleic Acids Res. 2012 Jan;40(Database issue):D1128-36. | |||||
| REF 9 | Montirelin hydrate (NS-3), a TRH analog, improved the disturbance of consciousness caused by head concussion and pentobarbital in mice. Nihon Yakurigaku Zasshi. 1996 May;107(5):237-45. | |||||
| REF 10 | TRH analogs at Gedeon Richter Ltd.: highlights of experimental and clinical efficacy of posatirelin. Acta Pharm Hung. 2002;72(1):62-8. | |||||
| REF 11 | Effect of JTP-2942, a novel thyrotropin-releasing hormone analogue, on pentobarbital-induced anesthesia in rats. Eur J Pharmacol. 1995 Mar 24;276(1-2):177-82. | |||||
| REF 12 | 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: 363). | |||||
| REF 13 | Corymbones A and B, phloroglucinols with thyrotropin releasing hormone receptor 2 binding affinity from the flowers of Corymbia peltata. J Nat Prod. 2008 May;71(5):881-3. | |||||
| REF 14 | Thyrotropin-releasing hormone receptor type 1 (TRH-R1), not TRH-R2, primarily mediates taltirelin actions in the CNS of mice. Neuropsychopharmacology. 2013 May;38(6):950-6. | |||||
| REF 15 | Preparation of 3H-[3-M3-His2]TRH as an improved ligand for TRH receptors. Neuroendocrinology. 1981 May;32(5):310-6. | |||||
| REF 16 | TRH analog MK-771 reverses neurochemical and learning deficits in medial septal-lesioned rats. Peptides. 1989 Jan-Feb;10(1):121-4. | |||||
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