Target Information
| Target General Information | Top | |||||
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| Target ID |
T76904
(Former ID: TTDS00362)
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| Target Name |
Catechol-O-methyl-transferase (COMT)
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| Synonyms |
S-COMT; MB-COMT; Catechol-O-methyltransferase; COMT
Click to Show/Hide
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| Gene Name |
COMT
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Parkinsonism [ICD-11: 8A00] | |||||
| Function |
Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol.
Click to Show/Hide
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| BioChemical Class |
Methyltransferase
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| UniProt ID | ||||||
| EC Number |
EC 2.1.1.6
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| Sequence |
MPEAPPLLLAAVLLGLVLLVVLLLLLRHWGWGLCLIGWNEFILQPIHNLLMGDTKEQRIL
NHVLQHAEPGNAQSVLEAIDTYCEQKEWAMNVGDKKGKIVDAVIQEHQPSVLLELGAYCG YSAVRMARLLSPGARLITIEINPDCAAITQRMVDFAGVKDKVTLVVGASQDIIPQLKKKY DVDTLDMVFLDHWKDRYLPDTLLLEECGLLRKGTVLLADNVICPGAPDFLAHVRGSSCFE CTHYQSFLEYREVVDGLEKAIYKGPGSEAGP Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| ADReCS ID | BADD_A06627 | |||||
| HIT2.0 ID | T03CZ8 | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | Entacapone | Drug Info | Approved | Parkinson disease | [3], [4] | |
| 2 | Opicapone | Drug Info | Approved | Parkinson disease | [5] | |
| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | Entacapone+levodopa+carbidopa | Drug Info | Phase 3 | Restless legs syndrome | [6] | |
| 2 | BIA 3-202 | Drug Info | Phase 2 | Parkinson disease | [7] | |
| 3 | CGP-28014 | Drug Info | Phase 2 | Major depressive disorder | [8] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | Nitecapone | Drug Info | Discontinued in Phase 2 | Pain | [9] | |
| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | PGX-200097 | Drug Info | Preclinical | Schizophrenia | [10] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 12 Inhibitor drugs | + | ||||
| 1 | Entacapone | Drug Info | [1], [11] | |||
| 2 | Opicapone | Drug Info | [5] | |||
| 3 | Entacapone+levodopa+carbidopa | Drug Info | [12] | |||
| 4 | BIA 3-202 | Drug Info | [13] | |||
| 5 | PGX-200097 | Drug Info | [15] | |||
| 6 | (3,4-DIHYDROXY-2-NITROPHENYL)(PHENYL)METHANONE | Drug Info | [16] | |||
| 7 | 1-(3,4-dihydroxy-2-nitrophenyl)-2-phenylethanone | Drug Info | [17] | |||
| 8 | 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenoxyethanone | Drug Info | [18] | |||
| 9 | 3,5-Dinitrocatechol | Drug Info | [19] | |||
| 10 | 5,6-dihydroxy-7-nitro-2,3-dihydroinden-1-one | Drug Info | [17] | |||
| 11 | 6,7-dihydroxy-8-nitro-1-tetralone | Drug Info | [17] | |||
| 12 | 7,8-dihydroxy-4-phenyl-2H-chromen-2-one | Drug Info | [16] | |||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | CGP-28014 | Drug Info | [8] | |||
| 2 | Nitecapone | Drug Info | [14] | |||
| 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: Ademetionine | Ligand Info | |||||
| Structure Description | Crystal Structure of Human 108M Catechol O-methyltransferase bound with S-adenosylmethionine and inhibitor dinitrocatechol | PDB:3BWY | ||||
| Method | X-ray diffraction | Resolution | 1.30 Å | Mutation | No | [20] |
| PDB Sequence |
GDTKEQRILN
11 HVLQHAEPGN21 AQSVLEAIDT31 YCEQKEWAMN41 VGDKKGKIVD51 AVIQEHQPSV 61 LLELGAYCGY71 SAVRMARLLS81 PGARLITIEI91 NPDCAAITQR101 MVDFAGMKDK 111 VTLVVGASQD121 IIPQLKKKYD131 VDTLDMVFLD141 HWKDRYLPDT151 LLLEECGLLR 161 KGTVLLADNV171 ICPGAPDFLA181 HVRGSSCFEC191 THYQSFLEYR201 EVVDGLEKAI 211 YKGP
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MET40
3.440
ASN41
3.721
VAL42
2.838
GLU64
3.935
GLY66
2.904
ALA67
3.582
TYR68
3.324
GLY70
4.543
TYR71
3.248
SER72
2.751
ILE89
3.692
GLU90
2.670
ILE91
3.221
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Sinefungin | Ligand Info | |||||
| Structure Description | Crystal structure of Human soluble catechol O-methyltransferase in complex with 3,5-dinitrocatechol and Sinefungin | PDB:6I3D | ||||
| Method | X-ray diffraction | Resolution | 1.45 Å | Mutation | No | [21] |
| PDB Sequence |
GDTKEQRILN
11 HVLQHAEPGN21 AQSVLEAIDT31 YCEQKEWAMN41 VGDKKGKIVD51 AVIQEHQPSV 61 LLELGAYCGY71 SAVRMARLLS81 PGARLITIEI91 NPDCAAITQR101 MVDFAGVKDK 111 VTLVVGASQD121 IIPQLKKKYD131 VDTLDMVFLD141 HWKDRYLPDT151 LLLEECGLLR 161 KGTVLLADNV171 ICPGAPDFLA181 HVRGSSCFEC191 THYQSFLEYR201 EVVDGLEKAI 211 YKGP
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MET40
3.367
ASN41
3.669
VAL42
2.841
GLU64
3.962
LEU65
4.995
GLY66
2.875
ALA67
3.530
TYR68
3.208
GLY70
4.489
TYR71
3.302
SER72
2.746
ILE89
3.591
GLU90
2.655
ILE91
3.247
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| 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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| Steroid hormone biosynthesis | hsa00140 | Affiliated Target |
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| Class: Metabolism => Lipid metabolism | Pathway Hierarchy | ||
| Tyrosine metabolism | hsa00350 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Dopaminergic synapse | hsa04728 | Affiliated Target |
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| Class: Organismal Systems => Nervous system | Pathway Hierarchy | ||
| Degree | 7 | Degree centrality | 7.52E-04 | Betweenness centrality | 5.35E-04 |
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| Closeness centrality | 1.75E-01 | Radiality | 1.28E+01 | Clustering coefficient | 2.38E-01 |
| Neighborhood connectivity | 5.71E+00 | Topological coefficient | 2.09E-01 | Eccentricity | 11 |
| 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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| BioCyc | [+] 3 BioCyc Pathways | + | ||||
| 1 | L-dopa degradation | |||||
| 2 | Dopamine degradation | |||||
| 3 | Noradrenaline and adrenaline degradation | |||||
| KEGG Pathway | [+] 4 KEGG Pathways | + | ||||
| 1 | Steroid hormone biosynthesis | |||||
| 2 | Tyrosine metabolism | |||||
| 3 | Metabolic pathways | |||||
| 4 | Dopaminergic synapse | |||||
| Panther Pathway | [+] 2 Panther Pathways | + | ||||
| 1 | Adrenaline and noradrenaline biosynthesis | |||||
| 2 | Dopamine receptor mediated signaling pathway | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Tyrosine Metabolism | |||||
| WikiPathways | [+] 7 WikiPathways | + | ||||
| 1 | Methylation Pathways | |||||
| 2 | Metapathway biotransformation | |||||
| 3 | Estrogen metabolism | |||||
| 4 | Biogenic Amine Synthesis | |||||
| 5 | Dopamine metabolism | |||||
| 6 | Phase II conjugation | |||||
| 7 | Neurotransmitter Clearance In The Synaptic Cleft | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Catechol-O-methyltransferase inhibitors in the management of Parkinson's disease. Semin Neurol. 2001;21(1):15-22. | |||||
| REF 2 | 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: 6646). | |||||
| REF 3 | Drugs used to treat Parkinson's disease, present status and future directions. CNS Neurol Disord Drug Targets. 2008 Oct;7(4):321-42. | |||||
| REF 4 | 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: 6647). | |||||
| REF 5 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020 | |||||
| REF 6 | Optimizing levodopa therapy for Parkinson's disease with levodopa/carbidopa/entacapone: implications from a clinical and patient perspective. Neuropsychiatr Dis Treat. 2008 February; 4(1): 39-47. | |||||
| REF 7 | Effects of nebicapone on levodopa pharmacokinetics, catechol-O-methyltransferase activity, and motor fluctuations in patients with Parkinson disease. Clin Neuropharmacol. 2008 Jan-Feb;31(1):2-18. | |||||
| REF 8 | CGP 28014, a new inhibitor of cerebral catechol-O-methylation with a non-catechol structure. Naunyn Schmiedebergs Arch Pharmacol. 1990 Sep;342(3):305-11. | |||||
| REF 9 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001267) | |||||
| REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024498) | |||||
| REF 11 | Entacapone: a catechol-O-methyltransferase inhibitor for the adjunctive treatment of Parkinson's disease. Clin Ther. 2001 Jun;23(6):802-32; discussion 771. | |||||
| REF 12 | Emerging drugs for restless legs syndrome. Expert Opin Emerg Drugs. 2005 Aug;10(3):537-52. | |||||
| REF 13 | Chemical synthesis and characterization of conjugates of a novel catechol-O-methyltransferase inhibitor. Bioconjug Chem. 2002 Sep-Oct;13(5):1112-8. | |||||
| REF 14 | Effect of a novel catechol-O-methyltransferase inhibitor, nitecapone, on the metabolism of L-dopa in healthy volunteers. Clin Neuropharmacol. 1990 Oct;13(5):436-47. | |||||
| REF 15 | Schizophrenia, "just the facts" 5. Treatment and prevention. Past, present, and future. Schizophr Res. 2010 Sep;122(1-3):1-23. | |||||
| REF 16 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 17 | Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase. J Med Chem. 2005 Dec 15;48(25):8070-8. | |||||
| REF 18 | Synthesis, biological evaluation, and molecular modeling studies of a novel, peripherally selective inhibitor of catechol-O-methyltransferase. J Med Chem. 2004 Dec 2;47(25):6207-17. | |||||
| REF 19 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 20 | Crystal structures of human 108V and 108M catechol O-methyltransferase. J Mol Biol. 2008 Jun 27;380(1):120-30. | |||||
| REF 21 | Equatorial Active Site Compaction and Electrostatic Reorganization in Catechol-O-methyltransferase. ACS Catal. 2019 May 3;9(5):4394-4401. | |||||
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