Target Information
| Target General Information | Top | |||||
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| Target ID |
T76846
(Former ID: TTDR00375)
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| Target Name |
Melanocortin receptor 3 (MC3R)
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| Synonyms |
MC3-R
Click to Show/Hide
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| Gene Name |
MC3R
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| Target Type |
Literature-reported target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Obesity [ICD-11: 5B80-5B81] | |||||
| 2 | Sexual dysfunction [ICD-11: HA00-HA01] | |||||
| 3 | Type 2 diabetes mellitus [ICD-11: 5A11] | |||||
| Function |
Receptor for MSH (alpha, beta and gamma) and ACTH. This receptor is mediated by G proteins which activate adenylate cyclase. Required for expression of anticipatory patterns of activity and wakefulness during periods of limited nutrient availability and for the normal regulation of circadian clock activity in the brain.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MNASCCLPSVQPTLPNGSEHLQAPFFSNQSSSAFCEQVFIKPEVFLSLGIVSLLENILVI
LAVVRNGNLHSPMYFFLCSLAVADMLVSVSNALETIMIAIVHSDYLTFEDQFIQHMDNIF DSMICISLVASICNLLAIAVDRYVTIFYALRYHSIMTVRKALTLIVAIWVCCGVCGVVFI VYSESKMVIVCLITMFFAMMLLMGTLYVHMFLFARLHVKRIAALPPADGVAPQQHSCMKG AVTITILLGVFIFCWAPFFLHLVLIITCPTNPYCICYTAHFNTYLVLIMCNSVIDPLIYA FRSLELRNTFREILCGCNGMNLG 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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| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | Melanotetan II | Drug Info | Preclinical | Type-2 diabetes | [1] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Agonist | [+] 1 Agonist drugs | + | ||||
| 1 | Melanotetan II | Drug Info | [1] | |||
| Inhibitor | [+] 38 Inhibitor drugs | + | ||||
| 1 | Ac-dR[CEHdFRWC]-NH2 | Drug Info | [2] | |||
| 2 | Ac-His-D-Phe-Arg-2-Nal-NHCH3 | Drug Info | [3] | |||
| 3 | Ac-Nle-c[Asp-His-DNal(2')-Pro-Trp-Lys]-NH2 | Drug Info | [4] | |||
| 4 | Ac-R[CEHdFRWC]-NH2 | Drug Info | [2] | |||
| 5 | Ac-Tyr-D-Phe-Arg-2-Nal-NHCH3 | Drug Info | [3] | |||
| 6 | Ac-YK[CEHdFRWC]-NH2 | Drug Info | [2] | |||
| 7 | Ac-YRMEHdFRWG-NH2 | Drug Info | [2] | |||
| 8 | Ac-YRMEHdFRWGSPPKD-NH2 | Drug Info | [2] | |||
| 9 | Ac-YR[CEH(d-2alpha-Nal)RWC]-NH2 | Drug Info | [2] | |||
| 10 | Ac-YR[CEH(pCl-dF)RWC]-NH2 | Drug Info | [2] | |||
| 11 | Ac-YR[CEHdFRWC]-NH2 | Drug Info | [2] | |||
| 12 | Ac-YR[CEHdFRWC]SPPKD-NH2 | Drug Info | [2] | |||
| 13 | Ac-[CEHdFRWC]-NH2 | Drug Info | [2] | |||
| 14 | AEKKDEGPYRMEHFRWGSPPKD | Drug Info | [2] | |||
| 15 | C[CO-(CH2)2-CO-Nle-D-Phe-Arg-Trp-Lys]-NH2 | Drug Info | [5] | |||
| 16 | C[CO-(CH2)3-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2 | Drug Info | [5] | |||
| 17 | C[CO-(CH2)3-CO-Pro-D-Phe-Arg-Trp-Lys]-NH2 | Drug Info | [5] | |||
| 18 | C[CO-2,3-pyrazine-CO-D-Phe-Arg-Trp-Lys]-NH2 | Drug Info | [5] | |||
| 19 | C[CO-o-C6H4-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2 | Drug Info | [5] | |||
| 20 | C[Nle-Arg-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [6] | |||
| 21 | C[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH2 | Drug Info | [6] | |||
| 22 | C[Nle-Asp-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [6] | |||
| 23 | C[Nle-Gln-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [6] | |||
| 24 | C[Nle-Glu-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [6] | |||
| 25 | C[Nle-Glu-D-Phe-Arg-Trp-Glu]-NH2 | Drug Info | [6] | |||
| 26 | C[Nle-His-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [6] | |||
| 27 | C[Nle-His-D-Phe-Arg-Trp-Glu]-NH2 | Drug Info | [6] | |||
| 28 | C[Nle-Nle-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [6] | |||
| 29 | C[Nle-Nle-D-Phe-Arg-Trp-Glu]-NH2 | Drug Info | [6] | |||
| 30 | C[Nle-Pro-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [6] | |||
| 31 | C[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [6] | |||
| 32 | C[Nle-Val-D-Phe-Arg-Trp-Glu]-NH2 | Drug Info | [6] | |||
| 33 | GPYRMEHFRWGSPPKD-NH2 | Drug Info | [2] | |||
| 34 | MK-10 | Drug Info | [7] | |||
| 35 | MK-11 | Drug Info | [7] | |||
| 36 | MK-9 | Drug Info | [5] | |||
| 37 | NDP-SYSMEHFRWGKPVG | Drug Info | [2] | |||
| 38 | Tic-D-Phe-Arg-2-Nal-NHCH3 | Drug Info | [9] | |||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | SHU9119 | Drug Info | [8] | |||
| 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 | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.84E-01 | Radiality | 1.31E+01 | Clustering coefficient | 1.00E+00 |
| Neighborhood connectivity | 1.10E+01 | Topological coefficient | 6.11E-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 Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Neuroactive ligand-receptor interaction | |||||
| 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 | Emerging drugs for obesity: linking novel biological mechanisms to pharmaceutical pipelines. Expert Opin Emerg Drugs. 2005 Aug;10(3):643-60. | |||||
| REF 2 | Discovery of a beta-MSH-derived MC-4R selective agonist. J Med Chem. 2005 May 5;48(9):3095-8. | |||||
| REF 3 | 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 4 | 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 5 | 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 6 | 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 7 | Novel cyclic templates of alpha-MSH give highly selective and potent antagonists/agonists for human melanocortin-3/4 receptors. J Med Chem. 2002 Jun 6;45(12):2644-50. | |||||
| REF 8 | Activation of melanocortin type 3 receptor as a molecular mechanism for adrenocorticotropic hormone efficacy in gouty arthritis. Arthritis Rheum. 2002 Oct;46(10):2765-75. | |||||
| REF 9 | 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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