Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTKWFB8)

• DTT Name: Catechol-O-methyl-transferase (COMT)
• Synonyms: S-COMT; MB-COMT; Catechol-O-methyltransferase; COMT
• Gene Name: COMT
• DTT Type: Successful target; [1]
• Related Disease: Parkinsonism [ICD-11: 8A00]
• BioChemical Class: Methyltransferase
• UniProt ID: COMT_HUMAN
• TTD ID: T76904
• EC Number: EC 2.1.1.6
• Sequence:
  MPEAPPLLLAAVLLGLVLLVVLLLLLRHWGWGLCLIGWNEFILQPIHNLLMGDTKEQRIL
  NHVLQHAEPGNAQSVLEAIDTYCEQKEWAMNVGDKKGKIVDAVIQEHQPSVLLELGAYCG
  YSAVRMARLLSPGARLITIEINPDCAAITQRMVDFAGVKDKVTLVVGASQDIIPQLKKKY
  DVDTLDMVFLDHWKDRYLPDTLLLEECGLLRKGTVLLADNVICPGAPDFLAHVRGSSCFE
  CTHYQSFLEYREVVDGLEKAIYKGPGSEAGP
• 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.
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Tyrosine metabolism (hsa00350)
  Metabolic pathways (hsa01100)
  Dopaminergic synapse (hsa04728)
• Reactome Pathway:
  Enzymatic degradation of dopamine by COMT (R-HSA-379397)
  Enzymatic degradation of Dopamine by monoamine oxidase (R-HSA-379398)
  Potential therapeutics for SARS (R-HSA-9679191)
  Methylation (R-HSA-156581)
• BioCyc Pathway: MetaCyc:HS01791-MON

Molecular Interaction Atlas (MIA) of This DTT

3 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Entacapone	DMLBVKQ	Parkinson disease	8A00.0	Approved	[2], [1]
Opicapone	DM1BKA6	Parkinson disease	8A00.0	Approved	[3]
Tolcapone	DM8MNVO	Parkinson disease	8A00.0	Approved	[1], [4]

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Entacapone+levodopa+carbidopa	DM7EOBQ	Parkinson disease	8A00.0	Phase 3	[5]
BIA 3-202	DMG3ON2	Parkinson disease	8A00.0	Phase 2	[6]
CGP-28014	DMYNTQV	Major depressive disorder	6A70.3	Phase 2	[7]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Nitecapone	DMSJYEX	Pain	MG30-MG3Z	Discontinued in Phase 2	[8]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PGX-200097	DM1A2UI	Schizophrenia	6A20	Preclinical	[9]

8 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(3,4-DIHYDROXY-2-NITROPHENYL)(PHENYL)METHANONE	DMTB41W	Discovery agent	N.A.	Investigative	[10]
1-(3,4-dihydroxy-2-nitrophenyl)-2-phenylethanone	DM9M5D1	Discovery agent	N.A.	Investigative	[11]
1-(3,4-dihydroxy-5-nitrophenyl)-2-phenoxyethanone	DMKI719	Discovery agent	N.A.	Investigative	[12]
3,5-Dinitrocatechol	DMBGSHD	Discovery agent	N.A.	Investigative	[13]
5,6-dihydroxy-7-nitro-2,3-dihydroinden-1-one	DM94V8D	Discovery agent	N.A.	Investigative	[11]
6,7-dihydroxy-8-nitro-1-tetralone	DM9JLUS	Discovery agent	N.A.	Investigative	[11]
7,8-dihydroxy-4-phenyl-2H-chromen-2-one	DMUB5E8	Discovery agent	N.A.	Investigative	[10]
BIA	DM4RZ9A	Non-insulin dependent diabetes	5A11	Investigative	[10]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Major depressive disorder	6A20	Pre-frontal cortex	4.34E-01	-0.08	-0.53
Parkinson's disease	8A00.0	Substantia nigra tissue	9.24E-02	0.17	1.09
Schizophrenia	6A20	Pre-frontal cortex	1.82E-01	0.03	0.11
Schizophrenia	6A20	Superior temporal cortex	1.25E-01	-0.04	-0.29

References

• [1] Catechol-O-methyltransferase inhibitors in the management of Parkinson's disease. Semin Neurol. 2001;21(1):15-22.
• [2] Entacapone: a catechol-O-methyltransferase inhibitor for the adjunctive treatment of Parkinson's disease. Clin Ther. 2001 Jun;23(6):802-32; discussion 771.
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [4] Tolcapone: a novel approach to Parkinson's disease. Am J Health Syst Pharm. 1999 Nov 1;56(21):2195-205.
• [5] Emerging drugs for restless legs syndrome. Expert Opin Emerg Drugs. 2005 Aug;10(3):537-52.
• [6] Chemical synthesis and characterization of conjugates of a novel catechol-O-methyltransferase inhibitor. Bioconjug Chem. 2002 Sep-Oct;13(5):1112-8.
• [7] 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.
• [8] 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.
• [9] Schizophrenia, "just the facts" 5. Treatment and prevention. Past, present, and future. Schizophr Res. 2010 Sep;122(1-3):1-23.
• [10] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [11] 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.
• [12] 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.
• [13] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.