Target Information
| Target General Information | Top | |||||
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| Target ID |
T35842
(Former ID: TTDR00530)
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| Target Name |
Melanocortin receptor 1 (MC1R)
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| Synonyms |
Melanotropin receptor; Melanocyte-stimulating hormone receptor; Melanocortin-1 receptor; MSHR; MSH-R; MC1-R
Click to Show/Hide
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| Gene Name |
MC1R
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Hypoactive sexual desire dysfunction [ICD-11: HA00] | |||||
| 2 | Inborn porphyrin/heme metabolism error [ICD-11: 5C58] | |||||
| Function |
The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Receptor for MSH (alpha, beta and gamma) and ACTH.
Click to Show/Hide
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MAVQGSQRRLLGSLNSTPTAIPQLGLAANQTGARCLEVSISDGLFLSLGLVSLVENALVV
ATIAKNRNLHSPMYCFICCLALSDLLVSGSNVLETAVILLLEAGALVARAAVLQQLDNVI DVITCSSMLSSLCFLGAIAVDRYISIFYALRYHSIVTLPRARRAVAAIWVASVVFSTLFI AYYDHVAVLLCLVVFFLAMLVLMAVLYVHMLARACQHAQGIARLHKRQRPVHQGFGLKGA VTLTILLGIFFLCWGPFFLHLTLIVLCPEHPTCGCIFKNFNLFLALIICNAIIDPLIYAF HSQELRRTLKEVLTCSW Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T31JL4 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | AP-1030 | Drug Info | Phase 1/2 | Metabolic disorder | [6], [7] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | AP-1030 | Drug Info | [8] | |||
| 2 | AP-1189 | Drug Info | [12] | |||
| Inhibitor | [+] 26 Inhibitor drugs | + | ||||
| 1 | Ac-dR[CEHdFRWC]-NH2 | Drug Info | [9] | |||
| 2 | Ac-His-D-Phe-Arg-2-Nal-NHCH3 | Drug Info | [10] | |||
| 3 | Ac-Nle-c[Asp-His-DNal(2')-Pro-Trp-Lys]-NH2 | Drug Info | [11] | |||
| 4 | Ac-R[CEHdFRWC]-NH2 | Drug Info | [9] | |||
| 5 | Ac-Tyr-D-Phe-Arg-2-Nal-NHCH3 | Drug Info | [10] | |||
| 6 | Ac-YK[CEHdFRWC]-NH2 | Drug Info | [9] | |||
| 7 | Ac-YRMEHdFRWG-NH2 | Drug Info | [9] | |||
| 8 | Ac-YRMEHdFRWGSPPKD-NH2 | Drug Info | [9] | |||
| 9 | Ac-YR[CEH(d-2alpha-Nal)RWC]-NH2 | Drug Info | [9] | |||
| 10 | Ac-YR[CEH(pCl-dF)RWC]-NH2 | Drug Info | [9] | |||
| 11 | Ac-YR[CEHdFRWC]-NH2 | Drug Info | [9] | |||
| 12 | Ac-YR[CEHdFRWC]SPPKD-NH2 | Drug Info | [9] | |||
| 13 | Ac-YR[CEHFRWC]-NH2 | Drug Info | [9] | |||
| 14 | Ac-[CEHdFRWC]-NH2 | Drug Info | [9] | |||
| 15 | AEKKDEGPYRMEHFRWGSPPKD | Drug Info | [9] | |||
| 16 | C[CO-2,3-pyrazine-CO-D-Phe-Arg-Trp-Lys]-NH2 | Drug Info | [13] | |||
| 17 | C[CO-o-C6H4-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2 | Drug Info | [13] | |||
| 18 | C[Nle-Arg-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [14] | |||
| 19 | C[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH2 | Drug Info | [14] | |||
| 20 | C[Nle-Gln-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [14] | |||
| 21 | C[Nle-Nle-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [14] | |||
| 22 | C[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [14] | |||
| 23 | D-Phe-Arg-2-Nal-NHCH3 | Drug Info | [15] | |||
| 24 | GPYRMEHFRWGSPPKD-NH2 | Drug Info | [9] | |||
| 25 | NDP-SYSMEHFRWGKPVG | Drug Info | [9] | |||
| 26 | Tic-D-Phe-Arg-2-Nal-NHCH3 | Drug Info | [16] | |||
| 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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| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Melanogenesis | hsa04916 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 2.02E-04 |
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| Closeness centrality | 1.80E-01 | Radiality | 1.30E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 8.50E+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 | ||
| 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 | Neuroactive ligand-receptor interaction | |||||
| 2 | Melanogenesis | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Peptide ligand-binding receptors | |||||
| 2 | G alpha (s) signalling events | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | GPCRs, Class A Rhodopsin-like | |||||
| 2 | Peptide GPCRs | |||||
| 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 | The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954. | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019 | |||||
| REF 3 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019 | |||||
| REF 4 | ClinicalTrials.gov (NCT04402489) A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Efficacy, Safety, and Tolerability of MT-7117 in Adults and Adolescents With Erythropoietic Protoporphyria or X-Linked Protoporphyria. U.S.National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT05466890) Phase 2a, Double-Blind, Randomized Adaptive Design, Placebo-Controlled, Parallel Group Study to Evaluate the Safety, Tolerability, Efficacy, PK and Biomarkers With Oral Colon Delivery PL8177 in Adult Subjects With Active Ulcerative Colitis. U.S.National Institutes of Health. | |||||
| 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. (Ligand id: 1322). | |||||
| REF 7 | ClinicalTrials.gov (NCT00464958) One Year Extension Study To Protocol C2/5/TZ:MS-05. U.S. National Institutes of Health. | |||||
| REF 8 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
| REF 9 | Discovery of a beta-MSH-derived MC-4R selective agonist. J Med Chem. 2005 May 5;48(9):3095-8. | |||||
| REF 10 | Design and synthesis of potent and selective 1,3,4-trisubstituted-2-oxopiperazine based melanocortin-4 receptor agonists. Bioorg Med Chem Lett. 2006 Sep 1;16(17):4668-73. | |||||
| REF 11 | Substitution of arginine with proline and proline derivatives in melanocyte-stimulating hormones leads to selectivity for human melanocortin 4 rece... J Med Chem. 2009 Jun 25;52(12):3627-35. | |||||
| 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: 282). | |||||
| REF 13 | Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 ... J Med Chem. 2008 Jan 24;51(2):187-95. | |||||
| REF 14 | Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities. J Med Chem. 2006 Mar 23;49(6):1946-52. | |||||
| REF 15 | Design, synthesis, and evaluation of proline and pyrrolidine based melanocortin receptor agonists. A conformationally restricted dipeptide mimic ap... J Med Chem. 2006 Jul 27;49(15):4745-61. | |||||
| REF 16 | Synthesis of Tic-D-Phe Psi[CH2-CH2] isostere and its use in the development of melanocortin receptor agonists. Bioorg Med Chem Lett. 2006 Mar 15;16(6):1721-5. | |||||
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