Target Information
| Target General Information | Top | |||||
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| Target ID |
T59604
(Former ID: TTDC00127)
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| Target Name |
Growth hormone secretagogue receptor 1 (GHSR)
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| Synonyms |
Growth hormone secretagogue receptor; Ghrelin receptor; GHSR; GHS-R; GHRP; GH-releasing peptide receptor
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| Gene Name |
GHSR
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Chronic pain [ICD-11: MG30] | |||||
| 2 | Pituitary gland disorder [ICD-11: 5A60-5A61] | |||||
| Function |
Receptor for ghrelin, coupled to G-alpha-11 proteins. Stimulates growth hormone secretion. Binds also other growth hormone releasing peptides (GHRP) (e.g. Met-enkephalin and GHRP-6) as well as non-peptide, low molecular weight secretagogues (e.g. L-692,429, MK-0677, adenosine).
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MWNATPSEEPGFNLTLADLDWDASPGNDSLGDELLQLFPAPLLAGVTATCVALFVVGIAG
NLLTMLVVSRFRELRTTTNLYLSSMAFSDLLIFLCMPLDLVRLWQYRPWNFGDLLCKLFQ FVSESCTYATVLTITALSVERYFAICFPLRAKVVVTKGRVKLVIFVIWAVAFCSAGPIFV LVGVEHENGTDPWDTNECRPTEFAVRSGLLTVMVWVSSIFFFLPVFCLTVLYSLIGRKLW RRRRGDAVVGASLRDQNHKQTVKMLAVVVFAFILCWLPFHVGRYLFSKSFEPGSLEIAQI SQYCNLVSFVLFYLSAAINPILYNIMSKKYRVAVFRLLGFEPFSQRKLSTLKDESSRAWT ESSINT Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T80MG0 | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 3 Approved Drugs | + | ||||
| 1 | GHRP-2 | Drug Info | Approved | Growth hormone deficiency | [2] | |
| 2 | Ibutamoren | Drug Info | Approved | Fibromyalgia | [3], [4] | |
| 3 | Macimorelin | Drug Info | Approved | Somatotropin deficiency | [5] | |
| Clinical Trial Drug(s) | [+] 5 Clinical Trial Drugs | + | ||||
| 1 | Anamorelin | Drug Info | Phase 3 | Carbohydrate metabolism disorder | [6] | |
| 2 | GTP-200 | Drug Info | Phase 2 | Solid tumour/cancer | [12] | |
| 3 | Ipamorelin | Drug Info | Phase 1/2 | Postoperative ileus | [8] | |
| 4 | PF-05190457 | Drug Info | Phase 1 | Type-2 diabetes | [13] | |
| 5 | ST-1141 | Drug Info | Phase 1 | Functional bowel disorder | [14] | |
| Discontinued Drug(s) | [+] 3 Discontinued Drugs | + | ||||
| 1 | CYT-009-GhrQb | Drug Info | Discontinued in Phase 1/2 | Obesity | [15] | |
| 2 | LY-444711 | Drug Info | Discontinued in Phase 1 | Growth hormone deficiency | [16] | |
| 3 | SUN-11031 | Drug Info | Terminated | Anorexia nervosa cachexia | [19] | |
| Preclinical Drug(s) | [+] 3 Preclinical Drugs | + | ||||
| 1 | AEZS-123 | Drug Info | Preclinical | Alcohol dependence | [17] | |
| 2 | EP-01492 | Drug Info | Preclinical | Obesity | [15] | |
| 3 | TZP-301 | Drug Info | Preclinical | Metabolic disorder | [18] | |
| Mode of Action | [+] 5 Modes of Action | + | ||||
| Agonist | [+] 9 Agonist drugs | + | ||||
| 1 | GHRP-2 | Drug Info | [20] | |||
| 2 | Macimorelin | Drug Info | [1] | |||
| 3 | GTP-200 | Drug Info | [24] | |||
| 4 | ST-1141 | Drug Info | [27] | |||
| 5 | LY-444711 | Drug Info | [28] | |||
| 6 | SUN-11031 | Drug Info | [19] | |||
| 7 | EX-1314 | Drug Info | [30] | |||
| 8 | SM-130,686 | Drug Info | [33] | |||
| 9 | [35S]ibutamoren | Drug Info | [35] | |||
| Modulator | [+] 3 Modulator drugs | + | ||||
| 1 | Ibutamoren | Drug Info | [21], [22] | |||
| 2 | Ipamorelin | Drug Info | [25] | |||
| 3 | PF-05190457 | Drug Info | [26] | |||
| Stimulator | [+] 1 Stimulator drugs | + | ||||
| 1 | Anamorelin | Drug Info | [23] | |||
| Antagonist | [+] 8 Antagonist drugs | + | ||||
| 1 | CYT-009-GhrQb | Drug Info | [15] | |||
| 2 | AEZS-123 | Drug Info | [17] | |||
| 3 | EP-01492 | Drug Info | [15] | |||
| 4 | TZP-301 | Drug Info | [18] | |||
| 5 | GSK1614343 | Drug Info | [31] | |||
| 6 | JMV3008 | Drug Info | [32] | |||
| 7 | NOX-B11 | Drug Info | [30] | |||
| 8 | YIL781 | Drug Info | [34] | |||
| Inhibitor | [+] 9 Inhibitor drugs | + | ||||
| 1 | AwFwLL-NH2 | Drug Info | [29] | |||
| 2 | DprwFwLL-NH2 | Drug Info | [29] | |||
| 3 | DwFwLL-NH2 | Drug Info | [29] | |||
| 4 | HwFwLL-NH2 | Drug Info | [29] | |||
| 5 | QwFwLL-NH2 | Drug Info | [29] | |||
| 6 | RPKPfQwFwLL-NH2 | Drug Info | [29] | |||
| 7 | RwFwLL-NH2 | Drug Info | [29] | |||
| 8 | WFwGG-NH2 | Drug Info | [29] | |||
| 9 | WFwLL-NH2 | Drug Info | [29] | |||
| 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: Ibutamoren | Ligand Info | |||||
| Structure Description | Structures of human ghrelin receptor-Gi complexes with ghrelin and a synthetic agonist | PDB:7NA8 | ||||
| Method | Electron microscopy | Resolution | 2.70 Å | Mutation | No | [36] |
| PDB Sequence |
PAPLLAGVTA
48 TCVALFVVGI58 AGNLLTMLVV68 SRFRELRTTT78 NLYLSSMAFS88 DLLIFLCMPL 98 DLVRLWQPWN110 FGDLLCKLFQ120 FVSESCTYAK130 VLTITALSVE140 RYFAICFPLR 150 AKVVVTKGRV160 KLVIFVIWAV170 AFCSAGPIFV180 LVGVEHEPWD194 TNECRPTEFA 204 VRSGLLTVMV214 WVSSIFFFLP224 VFCLTVLYSL234 IGRKLWRRRD255 QNHKQTVKML 265 AVVVFAFILC275 WLPFHVGRYL285 FSKSFEPGSL295 EIAQISQYCN305 LVSFVLFYLS 315 AAINPILYNI325 MSKKYRVAVF335 RLLGF
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ASP99
2.839
ARG102
2.909
LEU103
3.236
PHE119
4.197
GLN120
2.902
SER123
3.387
GLU124
3.262
TYR128
4.955
ILE178
3.396
LEU181
3.957
VAL182
4.912
CYS198
4.662
PRO200
4.672
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| Ligand Name: Cholesterol | Ligand Info | |||||
| Structure Description | Structures of human ghrelin receptor-Gi complexes with ghrelin and a synthetic agonist | PDB:7NA7 | ||||
| Method | Electron microscopy | Resolution | 2.70 Å | Mutation | Yes | [36] |
| PDB Sequence |
PAPLLAGVTA
48 TCVALFVVGI58 AGNLLTMLVV68 SRFRELRTTT78 NLYLSSMAFS88 DLLIFLCMPL 98 DLVRLWQYRP108 WNFGDLLCKL118 FQFVSESCTY128 AKVLTITALS138 VERYFAICFP 148 LRAKVVVTKG158 RVKLVIFVIW168 AVAFCSAGPI178 FVLVGVEHEQ188 GTDPWDTNEC 198 RPTEFAVRSG208 LLTVMVWVSS218 IFFFLPVFCL228 TVLYSLIGRK238 LWRRRDQNHK 259 QTVKMLAVVV269 FAFILCWLPF279 HVGRYLFSKS289 FEPGSLEIAQ299 ISQYCNLVSF 309 VLFYLSAAIN319 PILYNIMSKK329 YRVAVFRLLG339 F
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LEU80
3.910
TYR81
4.364
SER83
4.041
SER84
3.311
PHE87
3.542
LEU91
3.585
VAL122
4.919
LEU132
3.792
THR135
3.817
ALA136
3.721
VAL139
3.539
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| 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 |
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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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| cAMP signaling pathway | hsa04024 | 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 | ||
| Growth hormone synthesis, secretion and action | hsa04935 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 7.76E-05 |
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| Closeness centrality | 1.71E-01 | Radiality | 1.27E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 7.50E+00 | Topological coefficient | 5.00E-01 | Eccentricity | 13 |
| 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 | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| 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 | cAMP signaling pathway | |||||
| 2 | Neuroactive ligand-receptor interaction | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | Leptin 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 | ||||||
| References | Top | |||||
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| REF 1 | National Cancer Institute Drug Dictionary (drug id 735530). | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 3 | 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: 5867). | |||||
| REF 4 | Emerging therapies for fibromyalgia. Expert Opin Emerg Drugs. 2008 Mar;13(1):53-62. | |||||
| REF 5 | 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85. | |||||
| REF 6 | ClinicalTrials.gov (NCT01395914) Anamorelin HCl in the Treatment of Non-Small Cell Lung Cancer-Cachexia (NSCLC-C): An Extension Study (ROMANA 3). U.S. National Institutes of Health. | |||||
| REF 7 | 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: 3535). | |||||
| REF 8 | Emerging drugs for postoperative ileus. Expert Opin Emerg Drugs. 2007 Nov;12(4):619-26. | |||||
| REF 9 | Pharmacological characterisation of a new oral GH secretagogue, NN703. Eur J Endocrinol. 1999 Aug;141(2):180-9. | |||||
| REF 10 | ClinicalTrials.gov (NCT00527046) Effects Of An Oral Growth Hormone Secretagogue In Older Functionally Limited Adults. U.S. National Institutes of Health. | |||||
| REF 11 | ClinicalTrials.gov (NCT05364684) The Impact of Ibutamoren on Nonalcoholic Fatty Liver Disease: A Pilot Study. U.S.National Institutes of Health. | |||||
| REF 12 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800023682) | |||||
| REF 13 | ClinicalTrials.gov (NCT01522807) A Study Of Three PF-05190457 Formulations In Healthy Volunteers. U.S. National Institutes of Health. | |||||
| REF 14 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025998) | |||||
| REF 15 | Emerging drugs for obesity: linking novel biological mechanisms to pharmaceutical pipelines. Expert Opin Emerg Drugs. 2005 Aug;10(3):643-60. | |||||
| REF 16 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800012573) | |||||
| REF 17 | 2011 Pipeline of Aeterna Zentaris. | |||||
| REF 18 | Clinical pipeline report, company report or official report of Tranzyme Pharma (2011). | |||||
| REF 19 | Emerging drugs for eating disorder treatment. Expert Opin Emerg Drugs. 2006 May;11(2):315-36. | |||||
| REF 20 | GH-releasing peptide-2 increases fat mass in mice lacking NPY: indication for a crucial mediating role of hypothalamic agouti-related protein. Endocrinology. 2002 Feb;143(2):558-68. | |||||
| REF 21 | Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue. Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):7001-5. | |||||
| REF 22 | Identification of a new G-protein-linked receptor for growth hormone secretagogues. Mol Endocrinol. 1996 Jan;10(1):57-61. | |||||
| REF 23 | Pharmacodynamic hormonal effects of anamorelin, a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers. Growth Horm IGF Res. 2009 Jun;19(3):267-73. | |||||
| REF 24 | Orphan GPCR research. Br J Pharmacol. 2008 March; 153(Suppl 1): S339-S346. | |||||
| REF 25 | Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus.J Pharmacol Exp Ther.2009 Jun;329(3):1110-6. | |||||
| REF 26 | A gift for research. SciBX 7(6); doi:10.1038/scibx.2014.160. Feb. 13 2014 | |||||
| REF 27 | The Prokinetic Face of Ghrelin. International Journal of Peptides Volume 2010 (2010), Article ID 493614, Page(11). | |||||
| REF 28 | Synthesis and biological evaluation of an orally active ghrelin agonist that stimulates food consumption and adiposity in rats. Bioorg Med Chem Lett. 2004 Dec 6;14(23):5873-6. | |||||
| REF 29 | Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism. J Biol Chem. 2007 May 25;282(21):15799-811. | |||||
| REF 30 | 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: 246). | |||||
| REF 31 | Discovery process and characterization of novel carbohydrazide derivatives as potent and selective GHSR1a antagonists. ChemMedChem. 2010 Sep 3;5(9):1450-5. | |||||
| REF 32 | Toward potent ghrelin receptor ligands based on trisubstituted 1,2,4-triazole structure. 2. Synthesis and pharmacological in vitro and in vivo eval... J Med Chem. 2007 Nov 15;50(23):5790-806. | |||||
| REF 33 | Oxindole derivatives as orally active potent growth hormone secretagogues. J Med Chem. 2001 Dec 20;44(26):4641-9. | |||||
| REF 34 | Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss. Endocrinology. 2007 Nov;148(11):5175-85. | |||||
| REF 35 | Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol Endocrinol. 1997 Apr;11(4):415-23. | |||||
| REF 36 | Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren. doi:10.1038/s41467-021-26735-5. | |||||
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