Target Information
| Target General Information | Top | |||||
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| Target ID |
T32262
(Former ID: TTDC00093)
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| Target Name |
Calcitonin gene-related peptide receptor (CGRPR)
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| Synonyms |
Calcitonin receptor-like receptor; Calcitonin gene-related peptide type 1 receptor; CGRPR; CGRP type 1 receptor
Click to Show/Hide
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| Gene Name |
CALCRL
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Migraine [ICD-11: 8A80] | |||||
| 2 | Pituitary gland disorder [ICD-11: 5A60-5A61] | |||||
| Function |
Receptor for calcitonin-gene-related peptide (CGRP) together with RAMP1 and receptor for adrenomedullin together with RAMP3 (By similarity). Receptor for adrenomedullin together with RAMP2. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Click to Show/Hide
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| BioChemical Class |
GPCR secretin
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| UniProt ID | ||||||
| Sequence |
MEKKCTLNFLVLLPFFMILVTAELEESPEDSIQLGVTRNKIMTAQYECYQKIMQDPIQQA
EGVYCNRTWDGWLCWNDVAAGTESMQLCPDYFQDFDPSEKVTKICDQDGNWFRHPASNRT WTNYTQCNVNTHEKVKTALNLFYLTIIGHGLSIASLLISLGIFFYFKSLSCQRITLHKNL FFSFVCNSVVTIIHLTAVANNQALVATNPVSCKVSQFIHLYLMGCNYFWMLCEGIYLHTL IVVAVFAEKQHLMWYYFLGWGFPLIPACIHAIARSLYYNDNCWISSDTHLLYIIHGPICA ALLVNLFFLLNIVRVLITKLKVTHQAESNLYMKAVRATLILVPLLGIEFVLIPWRPEGKI AEEVYDYIMHILMHFQGLLVSTIFCFFNGEVQAILRRNWNQYKIQFGNSFSNSEALRSAS YTVSTISDGPGYSHDCPSEHLNGKSIHDIENVLLKPENLYN Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 5 Approved Drugs | + | ||||
| 1 | Atogepant | Drug Info | Approved | Migraine | [4] | |
| 2 | Erenumab | Drug Info | Approved | Hyperprolactinaemia | [5] | |
| 3 | Fremanezumab | Drug Info | Approved | Hyperprolactinaemia | [5] | |
| 4 | Galcanezumab | Drug Info | Approved | Hyperprolactinaemia | [5] | |
| 5 | Ubrogepant | Drug Info | Approved | Migraine | [6] | |
| Clinical Trial Drug(s) | [+] 5 Clinical Trial Drugs | + | ||||
| 1 | AMG 334 | Drug Info | Phase 2 | Migraine | [8] | |
| 2 | MK-3207 | Drug Info | Phase 2 | Migraine | [9] | |
| 3 | Olcegepant | Drug Info | Phase 2 | Migraine | [10], [11] | |
| 4 | Telcagepant | Drug Info | Phase 2 | Cluster headache | [12], [13] | |
| 5 | LBR-101 | Drug Info | Phase 1 | Migraine | [14] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Antagonist | [+] 4 Antagonist drugs | + | ||||
| 1 | Atogepant | Drug Info | [15] | |||
| 2 | Ubrogepant | Drug Info | [6] | |||
| 3 | MK-3207 | Drug Info | [17] | |||
| 4 | Telcagepant | Drug Info | [19], [20], [21] | |||
| Modulator | [+] 5 Modulator drugs | + | ||||
| 1 | Erenumab | Drug Info | [5] | |||
| 2 | Fremanezumab | Drug Info | [5] | |||
| 3 | Galcanezumab | Drug Info | [5] | |||
| 4 | AMG 334 | Drug Info | [16] | |||
| 5 | Olcegepant | Drug Info | [18] | |||
| Inhibitor | [+] 11 Inhibitor drugs | + | ||||
| 1 | BMS-694153 | Drug Info | [22] | |||
| 2 | EPIMER A | Drug Info | [23] | |||
| 3 | FV-Aib-TDVGPFAF | Drug Info | [24] | |||
| 4 | FV-Hyp-TDVGPFAF | Drug Info | [24] | |||
| 5 | FV-Tic-TDVGPFAF | Drug Info | [24] | |||
| 6 | FVATDVGPFAF | Drug Info | [24] | |||
| 7 | FVPTDVG-Tic-FAF-Tic | Drug Info | [24] | |||
| 8 | FVPTDVGAFAF | Drug Info | [24] | |||
| 9 | FVPTDVGPFAF | Drug Info | [24] | |||
| 10 | HCGRPalpha | Drug Info | [25] | |||
| 11 | ISOMER A | Drug Info | [23] | |||
| 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: Olcegepant | Ligand Info | |||||
| Structure Description | Crystal structure of the ectodomain complex of the CGRP receptor, a Class-B GPCR, reveals the site of drug antagonism | PDB:3N7S | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [26] |
| PDB Sequence |
IQLGVTRNKI
41 MTAQYECYQK51 IMQDPIEGVY64 CNRTWDGWLC74 WNDVAAGTES84 MQLCPDYFQD 94 FDPSEKVTKI104 CDQDGNWFRH114 PASNRTWTNY124 TQCN
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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 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
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There is no similarity protein (E value < 0.005) for this target
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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.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Vascular smooth muscle contraction | hsa04270 | Affiliated Target |
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| Class: Organismal Systems => Circulatory system | Pathway Hierarchy | ||
| Degree | 9 | Degree centrality | 9.67E-04 | Betweenness centrality | 1.35E-04 |
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| Closeness centrality | 1.80E-01 | Radiality | 1.30E+01 | Clustering coefficient | 4.17E-01 |
| Neighborhood connectivity | 9.11E+00 | Topological coefficient | 2.02E-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 Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Neuroactive ligand-receptor interaction | |||||
| 2 | Vascular smooth muscle contraction | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | G alpha (s) signalling events | |||||
| 2 | Calcitonin-like ligand receptors | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | GPCRs, Class B Secretin-like | |||||
| 2 | Endothelin Pathways | |||||
| 3 | GPCR ligand binding | |||||
| 4 | GPCR downstream signaling | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014 Feb;34(2):114-25. | |||||
| REF 2 | FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 216386. | |||||
| REF 3 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020 | |||||
| REF 4 | FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 215206. | |||||
| REF 5 | 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89. | |||||
| REF 6 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019 | |||||
| REF 7 | ClinicalTrials.gov (NCT00751803) BI 44370 TA in Acute Migraine Attack. U.S. National Institutes of Health. | |||||
| REF 8 | ClinicalTrials.gov (NCT02174861) A Study to Assess the Long-term Safety and Efficacy of AMG 334 in Chronic Migraine Prevention.. U.S. National Institutes of Health. | |||||
| REF 9 | ClinicalTrials.gov (NCT00712725) MK3207 for Treatment of Acute Migraines (3207-005). U.S. National Institutes of Health. | |||||
| REF 10 | 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: 702). | |||||
| REF 11 | ClinicalTrials.gov (NCT02198339) Efficacy, Safety, Tolerability and Pharmacokinetics of BIBN 4096 BS Versus Placebo in the Treatment of a Single Attack of Acute Migraine Headache. U.S. National Institutes of Health. | |||||
| 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. (Ligand id: 703). | |||||
| REF 13 | ACS chemical neuroscience molecule spotlight on Telcagepant (MK-0974). ACS Chem Neurosci. 2011 Jul 20;2(7):334-5. | |||||
| REF 14 | Safety and tolerability of LBR-101, a humanized monoclonal antibody that blocks the binding of CGRP to its receptor: Results of the Phase 1 program. Cephalalgia. 2013 Dec 23;34(7):483-492. | |||||
| REF 15 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 16 | EHMTI-0315. AMG 334, the first potent and selective human monoclonal antibody antagonist against the CGRP receptor. J Headache Pain. 2014; 15(Suppl 1): G43. | |||||
| REF 17 | Pharmacological properties of MK-3207, a potent and orally active calcitonin gene-related peptide receptor antagonist. J Pharmacol Exp Ther. 2010 Apr;333(1):152-60. | |||||
| REF 18 | Olcegepant, a non-peptide CGRP1 antagonist for migraine treatment. IDrugs. 2007 Aug;10(8):566-74. | |||||
| REF 19 | CGRP antagonists: novel concept for treatment of migraine. Med Monatsschr Pharm. 2009 May;32(5):182-5. | |||||
| REF 20 | Elimination of diastereomer interference to determine Telcagepant (MK-0974) in human plasma using on-line turbulent-flow technology and off-line so... J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Jun 1;877(16-17):1634-42. | |||||
| REF 21 | A flexible and high throughput liquid chromatography-tandem mass spectrometric assay for the quantitation of telcagepant in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2009 May 15;877(14-15):1465-71. | |||||
| REF 22 | Discovery of (R)-4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan... J Med Chem. 2008 Aug 28;51(16):4858-61. | |||||
| REF 23 | The identification of potent, orally bioavailable tricyclic CGRP receptor antagonists. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4740-2. | |||||
| REF 24 | Identification of the key residue of calcitonin gene related peptide (CGRP) 27-37 to obtain antagonists with picomolar affinity at the CGRP receptor. J Med Chem. 2006 Jan 26;49(2):616-24. | |||||
| REF 25 | cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain... J Med Chem. 2008 Nov 27;51(22):7094-8. | |||||
| REF 26 | Crystal structure of the ectodomain complex of the CGRP receptor, a class-B GPCR, reveals the site of drug antagonism. Structure. 2010 Sep 8;18(9):1083-93. | |||||
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