Target Information

Target General Infomation
Target ID
T57392
Former ID
TTDS00475
Target Name
Cytochrome P450 2D6
Gene Name
CYP2D6
Synonyms
CYP2DL1; CYPIID6; Debrisoquine 4-hydroxylase; P450-DB1; CYP2D6
Target Type
Successful
Disease Insomnia [ICD9: 307.41, 307.42, 327.0, 780.51, 780.52; ICD10: F51.0, G47.0]
Malaria [ICD10: B54]
Migraine [ICD9: 346; ICD10: G43]
Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
BioChemical Class
Oxidoreductases acting on paired donors
Target Validation
T57392
UniProt ID
P10635
EC Number
EC 1.14.14.1
Sequence
MGLEALVPLAVIVAIFLLLVDLMHRRQRWAARYPPGPLPLPGLGNLLHVDFQNTPYCFDQ
LRRRFGDVFSLQLAWTPVVVLNGLAAVREALVTHGEDTADRPPVPITQILGFGPRSQGVF
LARYGPAWREQRRFSVSTLRNLGLGKKSLEQWVTEEAACLCAAFANHSGRPFRPNGLLDK
AVSNVIASLTCGRRFEYDDPRFLRLLDLAQEGLKEESGFLREVLNAVPVLLHIPALAGKV
LRFQKAFLTQLDELLTEHRMTWDPAQPPRDLTEAFLAEMEKAKGNPESSFNDENLRIVVA
DLFSAGMVTTSTTLAWGLLLMILHPDVQRRVQQEIDDVIGQVRRPEMGDQAHMPYTTAVI
HEVQRFGDIVPLGVTHMTSRDIEVQGFRIPKGTTLITNLSSVLKDEAVWEKPFRFHPEHF
LDAQGHFVKPEAFLPFSAGRRACLGEPLARMELFLFFTSLLQHFSFSVPTGQPRPSHHGV
FAFLVSPSPYELCAVPR
Drugs and Mode of Action
Drug(s) Glutethimide Drug Info Approved Insomnia [535773], [542204]
ISOQUINE Drug Info Phase 1 Malaria [532126]
Inhibitor (2-hydroxy-3-phenoxypropyl)(propan-2-yl)amine Drug Info [527617]
(5-(pyridin-3-yl)furan-2-yl)methanamine Drug Info [528540]
(5-phenylfuran-2-yl)methanamine Drug Info [528540]
(5-pyridin-3-yl-furan-2-yl)methanethiol Drug Info [528540]
1,5-bis(4-hydroxyphenyl)penta-1,4-dien-3-one Drug Info [529286]
1-(3,4-DICHLOROPHENYL)-6-(METHOXYMETHYL)-3-AZABICYCLO[4.1.0]HEPTANE (ENANTIOMERIC MIX) Drug Info [530957]
1-(4-Butoxy-phenyl)-1H-imidazole Drug Info [526913]
1-(METHOXYMETHYL)-6-(NAPHTHALEN-2-YL)-3-AZABICYCLO[4.1.0]HEPTANE (ENANTIOMERIC MIX) Drug Info [530957]
1H-1,2,3-benzotriazol-1-amine Drug Info [526196]
2-(2-(4-tert-Butylphenylthio)ethyl)-1H-imidazole Drug Info [530846]
2-(4-Imidazol-1-yl-phenoxymethyl)-pyridine Drug Info [526913]
2-Fluoro-4-[5-(3-hydroxyphenyl)-2-thienyl]phenol Drug Info [530450]
2-Hexyloxy-5-imidazol-1-yl-pyridine Drug Info [526913]
2-[3-(4-Imidazol-1-yl-phenoxy)-propyl]-pyridine Drug Info [526913]
3-(6-Methoxynaphthalen-2-yl)pyridin-4-amine Drug Info [529624]
3-[3-(4-Imidazol-1-yl-phenoxy)-propyl]-pyridine Drug Info [526913]
4-(3-Pent-1-ynyl-benzyl)-1H-imidazole Drug Info [529437]
4-(3-Phenylethynyl-benzyl)-1H-imidazole Drug Info [529437]
4-(Spiro[chromene-2,4'-piperidine]-4-yl)benzamide Drug Info [530324]
4-methylaminomethyl-7-methoxycoumarin Drug Info [531159]
4-[2-(4-Imidazol-1-yl-phenoxy)-ethyl]-morpholine Drug Info [526913]
4-[3-(4-Imidazol-1-yl-phenoxy)-propyl]-pyridine Drug Info [526913]
4-[5-(3-Hydroxyphenyl)-2-thienyl)-2-methyl]phenol Drug Info [530450]
4-[5-(3-Hydroxyphenyl)-3-thienyl]-2-methylphenol Drug Info [530450]
6-(3,4-DICHLOROPHENYL)-1-[1-(METHYLOXY)-3-BUTEN-1-YL]-3-AZABICYCLO[4.1.0]HEPTANE (DIASTEREOMERIC MIX) Drug Info [530957]
Bis-(5-pyridin-3-yl-thiophen-2-ylmethyl)-amine Drug Info [527367]
BMS-694153 Drug Info [529618]
BS 7581 Drug Info [528130]
BS 7840 Drug Info [528130]
BS 9106 Drug Info [528130]
Desethyl isoquine Drug Info [529965]
DIHYDROCUBEBIN Drug Info [527404]
GB-12819 Drug Info [528130]
GBR 12530 Drug Info [528130]
GBR-12289 Drug Info [528130]
GNF-PF-2094 Drug Info [530517]
GNF-PF-4292 Drug Info [534050]
GNF-PF-5411 Drug Info [534050]
Go-Y022 Drug Info [529286]
ICI-199441 Drug Info [527541]
ISOQUINE Drug Info [529965]
Kaempferol-3-O-methyl ether Drug Info [527147]
Methyl-(5-pyridin-3-yl-thiophen-2-yl)-amine Drug Info [527367]
ML-3163 Drug Info [526668]
Prodipine Drug Info [534050]
SB-210313 Drug Info [534804]
Inducer Glutethimide Drug Info [536862], [537887]
Pathways
KEGG Pathway Metabolism of xenobiotics by cytochrome P450
Drug metabolism - cytochrome P450
Serotonergic synapse
Reactome Xenobiotics
WikiPathways Metapathway biotransformation
Tamoxifen metabolism
Oxidation by Cytochrome P450
Vitamin D Receptor Pathway
Aripiprazole Metabolic Pathway
Fatty Acid Omega Oxidation
Codeine and Morphine Metabolism
References
Ref 532126Antimalarial activity of isoquine against Kenyan Plasmodium falciparum clinical isolates and association with polymorphisms in pfcrt and pfmdr1 genes. J Antimicrob Chemother. 2013 Apr;68(4):786-8.
Ref 535773A comparison of the efficacy of aromatase inhibitors in second-line treatment of metastatic breast cancer. Am J Clin Oncol. 2003 Aug;26(4):S9-16.
Ref 542204(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: 7192).
Ref 526196Bioorg Med Chem Lett. 2001 Dec 3;11(23):2993-5.Discovery of a N'-hydroxyphenylformamidine derivative HET0016 as a potent and selective 20-HETE synthase inhibitor.
Ref 526668J Med Chem. 2003 Jul 17;46(15):3230-44.Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes.
Ref 526913Bioorg Med Chem Lett. 2004 Jan 19;14(2):333-6.Imidazole derivatives as new potent and selective 20-HETE synthase inhibitors.
Ref 527147J Nat Prod. 2004 Jul;67(7):1079-83.Sesquiterpenes and flavonol glycosides from Zingiber aromaticum and their CYP3A4 and CYP2D6 inhibitory activities.
Ref 527367J Med Chem. 2005 Jan 13;48(1):224-39.5-substituted, 6-substituted, and unsubstituted 3-heteroaromatic pyridine analogues of nicotine as selective inhibitors of cytochrome P-450 2A6.
Ref 527404J Nat Prod. 2005 Jan;68(1):64-8.Potent CYP3A4 inhibitory constituents of Piper cubeba.
Ref 527541Bioorg Med Chem Lett. 2005 May 16;15(10):2647-52.Arylacetamide kappa opioid receptor agonists with reduced cytochrome P450 2D6 inhibitory activity.
Ref 527617Bioorg Med Chem Lett. 2005 Sep 1;15(17):3816-20.A 3D-QSAR model for CYP2D6 inhibition in the aryloxypropanolamine series.
Ref 528130J Med Chem. 2006 Apr 20;49(8):2417-30.Catalytic site prediction and virtual screening of cytochrome P450 2D6 substrates by consideration of water and rescoring in automated docking.
Ref 528540J Med Chem. 2006 Nov 30;49(24):6987-7001.Synthetic inhibitors of cytochrome P-450 2A6: inhibitory activity, difference spectra, mechanism of inhibition, and protein cocrystallization.
Ref 529286Eur J Med Chem. 2008 Aug;43(8):1621-31. Epub 2007 Nov 17.Structure-activity relationships for the inhibition of recombinant human cytochromes P450 by curcumin analogues.
Ref 529437J Med Chem. 2008 May 22;51(10):2944-53. Epub 2008 Apr 24.4-benzyl-1H-imidazoles with oxazoline termini as histamine H3 receptor agonists.
Ref 529618J Med Chem. 2008 Aug 28;51(16):4858-61. Epub 2008 Jul 30.Discovery of (R)-4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide (BMS-694153): a potent antagonist of the human calcitonin gene-related peptide receptor for migraine with rapid and efficient intranasal exposure.
Ref 529624J Med Chem. 2008 Aug 28;51(16):5064-74. Epub 2008 Aug 1.Overcoming undesirable CYP1A2 inhibition of pyridylnaphthalene-type aldosterone synthase inhibitors: influence of heteroaryl derivatization onpotency and selectivity.
Ref 529965J Med Chem. 2009 Mar 12;52(5):1408-15.Candidate selection and preclinical evaluation of N-tert-butyl isoquine (GSK369796), an affordable and effective 4-aminoquinoline antimalarial for the 21st century.
Ref 530324J Med Chem. 2009 Sep 24;52(18):5685-702.Spirocyclic delta opioid receptor agonists for the treatment of pain: discovery of N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4'-piperidine]-4-yl) benzamide (ADL5747).
Ref 530450J Med Chem. 2009 Nov 12;52(21):6724-43.New insights into the SAR and binding modes of bis(hydroxyphenyl)thiophenes and -benzenes: influence of additional substituents on 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitory activity and selectivity.
Ref 530517Bioorg Med Chem Lett. 2010 Jan 1;20(1):228-31. Epub 2009 Oct 31.Synthesis and antiplasmodial activity of novel 2,4-diaminopyrimidines.
Ref 530846J Med Chem. 2010 May 13;53(9):3840-4.Role of hydrophobic substituents on the terminal nitrogen of histamine in receptor binding and agonist activity: development of an orally active histamine type 3 receptor agonist and evaluation of its antistress activity in mice.
Ref 530957J Med Chem. 2010 Jul 8;53(13):4989-5001.6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane: a new potent and selective triple reuptake inhibitor.
Ref 531159J Med Chem. 2010 Oct 14;53(19):7129-39.Exploration of the amine terminus in a novel series of 1,2,4-triazolo-3-yl-azabicyclo[3.1.0]hexanes as selective dopamine D3 receptor antagonists.
Ref 534050J Med Chem. 1993 Apr 30;36(9):1136-45.Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies.
Ref 534804Bioorg Med Chem Lett. 1998 Nov 17;8(22):3111-6.Pyrimidinylimidazole inhibitors of CSBP/p38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes.
Ref 536862A study of the effects of large doses of glutethimide that were used for self-poisoning during pregnancy on human fetuses. Toxicol Ind Health. 2008 Feb-Mar;24(1-2):69-78.
Ref 537887Neurosteroidogenesis in rat retinas. J Neurochem. 1994 Jul;63(1):86-96.

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