Target Information
Target General Information | Top | |||||
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Target ID |
T72458
(Former ID: TTDC00072)
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Target Name |
Melanocortin receptor 4 (MC4R)
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Synonyms |
MC4-R
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Gene Name |
MC4R
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 3 Target-related Diseases | + | ||||
1 | Hypoactive sexual desire dysfunction [ICD-11: HA00] | |||||
2 | Large intestine motility disorder [ICD-11: DB32] | |||||
3 | Obesity [ICD-11: 5B80-5B81] | |||||
Function |
Plays a central role in energy homeostasis and somatic growth. This receptor is mediated by G proteins that stimulate adenylate cyclase (cAMP). Receptor specific to the heptapeptide core common to adrenocorticotropic hormone and alpha-, beta-, and gamma-MSH.
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BioChemical Class |
GPCR rhodopsin
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UniProt ID | ||||||
Sequence |
MVNSTHRGMHTSLHLWNRSSYRLHSNASESLGKGYSDGGCYEQLFVSPEVFVTLGVISLL
ENILVIVAIAKNKNLHSPMYFFICSLAVADMLVSVSNGSETIVITLLNSTDTDAQSFTVN IDNVIDSVICSSLLASICSLLSIAVDRYFTIFYALQYHNIMTVKRVGIIISCIWAACTVS GILFIIYSDSSAVIICLITMFFTMLALMASLYVHMFLMARLHIKRIAVLPGTGAIRQGAN MKGAITLTILIGVFVVCWAPFFLHLIFYISCPQNPYCVCFMSHFNLYLILIMCNSIIDPL IYALRSQELRKTFKEIICCYPLGGLCDLSSRY Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T17TKM |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 3 Approved Drugs | + | ||||
1 | Bremelanotide | Drug Info | Approved | Hypoactive sexual desire dysfunction | [2] | |
2 | Methylnaltrexone bromide | Drug Info | Approved | Opioid-induced constipation | [3] | |
3 | Setmelanotide | Drug Info | Approved | Obesity | [4] | |
Clinical Trial Drug(s) | [+] 4 Clinical Trial Drugs | + | ||||
1 | AMG 386 | Drug Info | Phase 3 | Neuropathic pain | [5] | |
2 | PF-446687 | Drug Info | Phase 2 | Female sexual arousal dysfunction | [6] | |
3 | PMX-53 | Drug Info | Phase 2 | Atopic dermatitis | [7], [8] | |
4 | AP-1030 | Drug Info | Phase 1/2 | Metabolic disorder | [9], [10] | |
Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
1 | PT-14 | Drug Info | Discontinued in Phase 2 | Erectile dysfunction | [11] | |
Preclinical Drug(s) | [+] 3 Preclinical Drugs | + | ||||
1 | IDDBCP-150101 | Drug Info | Preclinical | Sexual dysfunction | [1] | |
2 | Melanotetan II | Drug Info | Preclinical | Type-2 diabetes | [1] | |
3 | Ro-27-3225 | Drug Info | Preclinical | Obesity | [1] | |
Mode of Action | [+] 4 Modes of Action | + | ||||
Agonist | [+] 12 Agonist drugs | + | ||||
1 | Bremelanotide | Drug Info | [2] | |||
2 | Methylnaltrexone bromide | Drug Info | [1] | |||
3 | Setmelanotide | Drug Info | [4] | |||
4 | Amylin | Drug Info | [12] | |||
5 | AMG 386 | Drug Info | [1] | |||
6 | PT-14 | Drug Info | [16] | |||
7 | IDDBCP-150101 | Drug Info | [1] | |||
8 | Melanotetan II | Drug Info | [1] | |||
9 | Ro-27-3225 | Drug Info | [1] | |||
10 | AMSH | Drug Info | [23] | |||
11 | MT-II | Drug Info | [22], [23], [35] | |||
12 | THIQ | Drug Info | [24] | |||
Modulator | [+] 2 Modulator drugs | + | ||||
1 | PF-446687 | Drug Info | [13] | |||
2 | AP-1030 | Drug Info | [15] | |||
Inhibitor | [+] 64 Inhibitor drugs | + | ||||
1 | PMX-53 | Drug Info | [14] | |||
2 | 1-Benzyl-4-methyl-piperazine | Drug Info | [17] | |||
3 | 1-Methyl-4-(1-phenyl-ethyl)-piperazine | Drug Info | [17] | |||
4 | 4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one | Drug Info | [18] | |||
5 | Ac-dR[CEHdFRWC]-NH2 | Drug Info | [19] | |||
6 | Ac-His-D-Phe-Arg-2-Nal-NHCH3 | Drug Info | [20] | |||
7 | Ac-His-DPhe-Arg-Trp-NH2 | Drug Info | [21] | |||
8 | Ac-Nle-c[Asp-His-DNaI(2')-Pro-Trp-Lys]-NH2 | Drug Info | [22] | |||
9 | Ac-Nle-c[Asp-His-DNal(2')-Pro-Trp-Lys]-NH2 | Drug Info | [22] | |||
10 | AC-Nle-c[Asp-His-DPhe-Pro-Trp-Lys]-NH2 | Drug Info | [22] | |||
11 | Ac-R[CEHdFRWC]-NH2 | Drug Info | [19] | |||
12 | Ac-Tyr-D-Phe-Arg-2-Nal-NHCH3 | Drug Info | [20] | |||
13 | Ac-YCit[CEHdFRWC]-NH2 | Drug Info | [19] | |||
14 | Ac-YK[CEHdFRWC]-NH2 | Drug Info | [19] | |||
15 | Ac-YRC(Me)*EHdFRWC(Me)NH2 | Drug Info | [19] | |||
16 | Ac-YRMEHdFRWG-NH2 | Drug Info | [19] | |||
17 | Ac-YRMEHdFRWGSPPKD-NH2 | Drug Info | [19] | |||
18 | Ac-YR[CE(1-Me-H)dFRWC]-NH2 | Drug Info | [19] | |||
19 | Ac-YR[CEH(d-2alpha-Nal)RWC]-NH2 | Drug Info | [19] | |||
20 | Ac-YR[CEH(pCl-dF)RWC]-NH2 | Drug Info | [19] | |||
21 | Ac-YR[CEH(pF-dF)RWC]-NH2 | Drug Info | [19] | |||
22 | Ac-YR[CEHdFRWC]-NH2 | Drug Info | [19] | |||
23 | Ac-YR[CEHdFRWC]SPPKD-NH2 | Drug Info | [19] | |||
24 | Ac-YR[CEHFRWC]-NH2 | Drug Info | [19] | |||
25 | Ac-[CEHdFRWC]-NH2 | Drug Info | [19] | |||
26 | AEKKDEGPYRMEHFRWGSPPKD | Drug Info | [19] | |||
27 | C(his-D-phe-arg-trp-Abu) | Drug Info | [25] | |||
28 | C(his-D-phe-arg-trp-Ahp) | Drug Info | [25] | |||
29 | C(his-D-phe-arg-trp-Ahx) | Drug Info | [25] | |||
30 | C(his-D-phe-arg-trp-Aoc) | Drug Info | [25] | |||
31 | C(his-L-phe-arg-trp-Aoc) | Drug Info | [25] | |||
32 | C[CO-(CH2)2-CO-Nle-D-Nal(2)-Arg-Trp-Lys]-NH2 | Drug Info | [26] | |||
33 | C[CO-(CH2)2-CO-Nle-D-Phe-Arg-Trp-Lys]-NH2 | Drug Info | [26] | |||
34 | C[CO-(CH2)3-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2 | Drug Info | [26] | |||
35 | C[CO-o-C6H4-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2 | Drug Info | [26] | |||
36 | C[CO-o-C6H4-CO-Pro-D-Phe-Arg-Trp-Lys]-NH2 | Drug Info | [26] | |||
37 | C[Nle-Arg-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [27] | |||
38 | C[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH2 | Drug Info | [27] | |||
39 | C[Nle-Asp-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [27] | |||
40 | C[Nle-Asp-D-Phe-Arg-Trp-Glu]-NH2 | Drug Info | [27] | |||
41 | C[Nle-Gln-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [27] | |||
42 | C[Nle-Glu-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [27] | |||
43 | C[Nle-His-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [27] | |||
44 | C[Nle-His-D-Phe-Arg-Trp-Glu]-NH2 | Drug Info | [27] | |||
45 | C[Nle-Nle-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [27] | |||
46 | C[Nle-Nle-D-Phe-Arg-Trp-Glu]-NH2 | Drug Info | [27] | |||
47 | C[Nle-Pro-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [27] | |||
48 | C[Nle-Pro-D-Phe-Arg-Trp-Glu]-NH2 | Drug Info | [27] | |||
49 | C[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH2 | Drug Info | [27] | |||
50 | C[Nle-Val-D-Phe-Arg-Trp-Glu]-NH2 | Drug Info | [27] | |||
51 | C[Ser-Tyr-Thr-His-Dphe-Arg-Trp-Thr-Ile-Pro] | Drug Info | [28] | |||
52 | C[Thr-Tyr-Thr-His-DNaf-Arg-Trp-Thr-Ile-Pro] | Drug Info | [28] | |||
53 | D-Phe-Arg-2-Nal-NHCH3 | Drug Info | [29] | |||
54 | GPYRMEHFRWGSPPKD-NH2 | Drug Info | [19] | |||
55 | His-DPhe-Arg-Trp | Drug Info | [30] | |||
56 | Hoo-Phe-Orn-Pro-hle-Pff-Phe-NH2 | Drug Info | [14] | |||
57 | MCL-129 | Drug Info | [32] | |||
58 | MK-10 | Drug Info | [34] | |||
59 | MK-11 | Drug Info | [34] | |||
60 | ML-253764 | Drug Info | [28] | |||
61 | NDP-alpha-MSH | Drug Info | [36] | |||
62 | NDP-SYSMEHFRWGKPVG | Drug Info | [19] | |||
63 | Ser-Tyr-Ser-Nle-Glu-His-Dphe-Arg | Drug Info | [30] | |||
64 | Tic-D-Phe-Arg-2-Nal-NHCH3 | Drug Info | [37] | |||
Antagonist | [+] 4 Antagonist drugs | + | ||||
1 | BL-6020 | Drug Info | [24] | |||
2 | HS014 | Drug Info | [31] | |||
3 | MCL0129 | Drug Info | [24] | |||
4 | Melanocortin-4 Receptor antagonist | Drug Info | [33] |
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 | [+] 1 KEGG Pathways | + | ||||
1 | Neuroactive ligand-receptor interaction | |||||
PID Pathway | [+] 1 PID Pathways | + | ||||
1 | Syndecan-3-mediated signaling events | |||||
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 | ||||||
Target QSAR Model |
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 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019 | |||||
REF 3 | 2008 FDA drug approvals. Nat Rev Drug Discov. 2009 Feb;8(2):93-6. | |||||
REF 4 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020 | |||||
REF 5 | Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26. | |||||
REF 6 | ClinicalTrials.gov (NCT00862888) Study to Investigate Effect of a New Drug (PF-00446687) in Males Suffering From Erectile Dysfunction. 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: 579). | |||||
REF 8 | PMX-53 as a dual CD88 antagonist and an agonist for Mas-related gene 2 (MrgX2) in human mast cells. Mol Pharmacol. 2011 Jun;79(6):1005-13. | |||||
REF 9 | 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 10 | ClinicalTrials.gov (NCT00464958) One Year Extension Study To Protocol C2/5/TZ:MS-05. U.S. National Institutes of Health. | |||||
REF 11 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010143) | |||||
REF 12 | Novel anti-obesity drugs. Expert Opin Investig Drugs. 2000 Jun;9(6):1317-26. | |||||
REF 13 | Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole. Neuropsychopharmacology. 2015 Jul;40(8):1856-65. | |||||
REF 14 | Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: increased receptor specificity and in vivo activity. Bioorg Med Chem Lett. 2006 Oct 1;16(19):5088-92. | |||||
REF 15 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
REF 16 | The protective effects of the melanocortin receptor (MCR) agonist, melanotan-II (MTII), against binge-like ethanol drinking are facilitated by deletion of the MC3 receptor in mice. Neuropeptides. 2014 Feb;48(1):47-51. | |||||
REF 17 | Privileged structure based ligands for melanocortin receptors--substituted benzylic piperazine derivatives. Bioorg Med Chem Lett. 2005 Nov 15;15(22):4973-8. | |||||
REF 18 | Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 rec... J Med Chem. 2010 Sep 9;53(17):6386-97. | |||||
REF 19 | Discovery of a beta-MSH-derived MC-4R selective agonist. J Med Chem. 2005 May 5;48(9):3095-8. | |||||
REF 20 | 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 21 | Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R. J Med Chem. 1997 Jul 4;40(14):2133-9. | |||||
REF 22 | 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 23 | Designing drugs for the treatment of female sexual dysfunction. Drug Discov Today. 2007 Sep;12(17-18):757-66. | |||||
REF 24 | 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: 285). | |||||
REF 25 | Design of cyclic peptides with agonist activity at melanocortin receptor-4. Bioorg Med Chem Lett. 2006 Jul 15;16(14):3723-6. | |||||
REF 26 | 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 27 | 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 28 | Mapping the binding site of melanocortin 4 receptor agonists: a hydrophobic pocket formed by I3.28(125), I3.32(129), and I7.42(291) is critical for... J Med Chem. 2006 Feb 9;49(3):911-22. | |||||
REF 29 | 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 30 | Squalene-derived flexible linkers for bioactive peptides. Bioorg Med Chem Lett. 2007 Jun 15;17(12):3310-3. | |||||
REF 31 | Long-term administration of MC4 receptor antagonist HS014 causes hyperphagia and obesity in rats. Neuroreport. 1999 Mar 17;10(4):707-11. | |||||
REF 32 | Structure-activity relationships of novel piperazines as antagonists for the melanocortin-4 receptor. Bioorg Med Chem. 2007 Mar 1;15(5):1989-2005. | |||||
REF 33 | Emerging drugs for eating disorder treatment. Expert Opin Emerg Drugs. 2006 May;11(2):315-36. | |||||
REF 34 | 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 35 | Molecular determinants of ligand binding to the human melanocortin-4 receptor. Biochemistry. 2000 Dec 5;39(48):14900-11. | |||||
REF 36 | 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 37 | 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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