Target Information

Target General Information

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Target ID

T57392 (Former ID: TTDS00475)

Target Name

Debrisoquine 4-hydroxylase (CYP2D6)

Synonyms

P450-DB1; Cytochrome P450-DB1; Cytochrome P450 2D6; CYPIID6; CYP2DL1

Gene Name

CYP2D6

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Insomnia [ICD-11: 7A00-7A0Z]

Function

It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants. Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes.

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BioChemical Class

Paired donor oxygen oxidoreductase

UniProt ID

CP2D6_HUMAN

EC Number

EC 1.14.14.-

Sequence

MGLEALVPLAVIVAIFLLLVDLMHRRQRWAARYPPGPLPLPGLGNLLHVDFQNTPYCFDQ
LRRRFGDVFSLQLAWTPVVVLNGLAAVREALVTHGEDTADRPPVPITQILGFGPRSQGVF
LARYGPAWREQRRFSVSTLRNLGLGKKSLEQWVTEEAACLCAAFANHSGRPFRPNGLLDK
AVSNVIASLTCGRRFEYDDPRFLRLLDLAQEGLKEESGFLREVLNAVPVLLHIPALAGKV
LRFQKAFLTQLDELLTEHRMTWDPAQPPRDLTEAFLAEMEKAKGNPESSFNDENLRIVVA
DLFSAGMVTTSTTLAWGLLLMILHPDVQRRVQQEIDDVIGQVRRPEMGDQAHMPYTTAVI
HEVQRFGDIVPLGVTHMTSRDIEVQGFRIPKGTTLITNLSSVLKDEAVWEKPFRFHPEHF
LDAQGHFVKPEAFLPFSAGRRACLGEPLARMELFLFFTSLLQHFSFSVPTGQPRPSHHGV
FAFLVSPSPYELCAVPR

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3D Structure

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PDB

ADReCS ID

BADD_A00232 ; BADD_A00323 ; BADD_A00378 ; BADD_A01205 ; BADD_A01334 ; BADD_A01338 ; BADD_A01965 ; BADD_A01976 ; BADD_A02053 ; BADD_A02189 ; BADD_A02978 ; BADD_A03487 ; BADD_A03957 ; BADD_A04155 ; BADD_A04234 ; BADD_A04424 ; BADD_A05280 ; BADD_A05962 ; BADD_A06157 ; BADD_A06627

HIT2.0 ID

T11ZYR

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Glutethimide

Drug Info

Approved

Insomnia

[2], [3]

Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

ISOQUINE

Drug Info

Phase 1

Malaria

[4]

Mode of Action

[+] 2 Modes of Action

Inducer

[+] 1 Inducer drugs

Glutethimide

Drug Info

[1], [5]

Inhibitor

[+] 46 Inhibitor drugs

ISOQUINE

Drug Info

[6]

(2-hydroxy-3-phenoxypropyl)(propan-2-yl)amine

Drug Info

[7]

(5-(pyridin-3-yl)furan-2-yl)methanamine

Drug Info

[8]

(5-phenylfuran-2-yl)methanamine

Drug Info

[8]

(5-pyridin-3-yl-furan-2-yl)methanethiol

Drug Info

[8]

1,5-bis(4-hydroxyphenyl)penta-1,4-dien-3-one

Drug Info

[9]

1-(3,4-DICHLOROPHENYL)-6-(METHOXYMETHYL)-3-AZABICYCLO[4.1.0]HEPTANE (ENANTIOMERIC MIX)

Drug Info

[10]

1-(4-Butoxy-phenyl)-1H-imidazole

Drug Info

[11]

1-(METHOXYMETHYL)-6-(NAPHTHALEN-2-YL)-3-AZABICYCLO[4.1.0]HEPTANE (ENANTIOMERIC MIX)

Drug Info

[10]

1H-1,2,3-benzotriazol-1-amine

Drug Info

[12]

2-(2-(4-tert-Butylphenylthio)ethyl)-1H-imidazole

Drug Info

[13]

2-(4-Imidazol-1-yl-phenoxymethyl)-pyridine

Drug Info

[11]

2-Fluoro-4-[5-(3-hydroxyphenyl)-2-thienyl]phenol

Drug Info

[14]

2-Hexyloxy-5-imidazol-1-yl-pyridine

Drug Info

[11]

2-[3-(4-Imidazol-1-yl-phenoxy)-propyl]-pyridine

Drug Info

[11]

3-(6-Methoxynaphthalen-2-yl)pyridin-4-amine

Drug Info

[15]

3-[3-(4-Imidazol-1-yl-phenoxy)-propyl]-pyridine

Drug Info

[11]

4-(3-Pent-1-ynyl-benzyl)-1H-imidazole

Drug Info

[16]

4-(3-Phenylethynyl-benzyl)-1H-imidazole

Drug Info

[16]

4-(Spiro[chromene-2,4'-piperidine]-4-yl)benzamide

Drug Info

[17]

4-methylaminomethyl-7-methoxycoumarin

Drug Info

[18]

4-[2-(4-Imidazol-1-yl-phenoxy)-ethyl]-morpholine

Drug Info

[11]

4-[3-(4-Imidazol-1-yl-phenoxy)-propyl]-pyridine

Drug Info

[11]

4-[5-(3-Hydroxyphenyl)-2-thienyl)-2-methyl]phenol

Drug Info

[14]

4-[5-(3-Hydroxyphenyl)-3-thienyl]-2-methylphenol

Drug Info

[14]

6-(3,4-DICHLOROPHENYL)-1-[1-(METHYLOXY)-3-BUTEN-1-YL]-3-AZABICYCLO[4.1.0]HEPTANE (DIASTEREOMERIC MIX)

Drug Info

[10]

Bis-(5-pyridin-3-yl-thiophen-2-ylmethyl)-amine

Drug Info

[19]

BMS-694153

Drug Info

[20]

BS 7581

Drug Info

[21]

BS 7840

Drug Info

[21]

BS 9106

Drug Info

[21]

Desethyl isoquine

Drug Info

[6]

DIHYDROCUBEBIN

Drug Info

[22]

GB-12819

Drug Info

[21]

GBR 12530

Drug Info

[21]

GBR-12289

Drug Info

[21]

GNF-PF-2094

Drug Info

[23]

GNF-PF-4292

Drug Info

[24]

GNF-PF-5411

Drug Info

[24]

Go-Y022

Drug Info

[9]

ICI-199441

Drug Info

[25]

Kaempferol-3-O-methyl ether

Drug Info

[26]

Methyl-(5-pyridin-3-yl-thiophen-2-yl)-amine

Drug Info

[19]

ML-3163

Drug Info

[27]

Prodipine

Drug Info

[24]

SB-210313

Drug Info

[28]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"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

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating Transcription Factors

Target-regulating Transcription Factors Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

Metabolism of xenobiotics by cytochrome P450

Drug metabolism - cytochrome P450

Serotonergic synapse

Reactome

[+] 1 Reactome Pathways

Xenobiotics

WikiPathways

[+] 7 WikiPathways

Metapathway biotransformation

Tamoxifen metabolism

Oxidation by Cytochrome P450

Vitamin D Receptor Pathway

Aripiprazole Metabolic Pathway

Fatty Acid Omega Oxidation

Codeine and Morphine Metabolism

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

A 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 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: 7192).

REF 3

A 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 4

Antimalarial 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 5

Neurosteroidogenesis in rat retinas. J Neurochem. 1994 Jul;63(1):86-96.

REF 6

Candidate selection and preclinical evaluation of N-tert-butyl isoquine (GSK369796), an affordable and effective 4-aminoquinoline antimalarial for ... J Med Chem. 2009 Mar 12;52(5):1408-15.

REF 7

A 3D-QSAR model for CYP2D6 inhibition in the aryloxypropanolamine series. Bioorg Med Chem Lett. 2005 Sep 1;15(17):3816-20.

REF 8

Synthetic inhibitors of cytochrome P-450 2A6: inhibitory activity, difference spectra, mechanism of inhibition, and protein cocrystallization. J Med Chem. 2006 Nov 30;49(24):6987-7001.

REF 9

Structure-activity relationships for the inhibition of recombinant human cytochromes P450 by curcumin analogues. Eur J Med Chem. 2008 Aug;43(8):1621-31.

REF 10

6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane: a new potent and selective triple reuptake inhibitor. J Med Chem. 2010 Jul 8;53(13):4989-5001.

REF 11

Imidazole derivatives as new potent and selective 20-HETE synthase inhibitors. Bioorg Med Chem Lett. 2004 Jan 19;14(2):333-6.

REF 12

Discovery of a N'-hydroxyphenylformamidine derivative HET0016 as a potent and selective 20-HETE synthase inhibitor. Bioorg Med Chem Lett. 2001 Dec 3;11(23):2993-5.

REF 13

Role of hydrophobic substituents on the terminal nitrogen of histamine in receptor binding and agonist activity: development of an orally active hi... J Med Chem. 2010 May 13;53(9):3840-4.

REF 14

New insights into the SAR and binding modes of bis(hydroxyphenyl)thiophenes and -benzenes: influence of additional substituents on 17beta-hydroxyst... J Med Chem. 2009 Nov 12;52(21):6724-43.

REF 15

Overcoming undesirable CYP1A2 inhibition of pyridylnaphthalene-type aldosterone synthase inhibitors: influence of heteroaryl derivatization on pote... J Med Chem. 2008 Aug 28;51(16):5064-74.

REF 16

4-benzyl-1H-imidazoles with oxazoline termini as histamine H3 receptor agonists. J Med Chem. 2008 May 22;51(10):2944-53.

REF 17

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) b... J Med Chem. 2009 Sep 24;52(18):5685-702.

REF 18

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. J Med Chem. 2010 Oct 14;53(19):7129-39.

REF 19

5-substituted, 6-substituted, and unsubstituted 3-heteroaromatic pyridine analogues of nicotine as selective inhibitors of cytochrome P-450 2A6. J Med Chem. 2005 Jan 13;48(1):224-39.

REF 20

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... J Med Chem. 2008 Aug 28;51(16):4858-61.

REF 21

Catalytic site prediction and virtual screening of cytochrome P450 2D6 substrates by consideration of water and rescoring in automated docking. J Med Chem. 2006 Apr 20;49(8):2417-30.

REF 22

Potent CYP3A4 inhibitory constituents of Piper cubeba. J Nat Prod. 2005 Jan;68(1):64-8.

REF 23

Synthesis and antiplasmodial activity of novel 2,4-diaminopyrimidines. Bioorg Med Chem Lett. 2010 Jan 1;20(1):228-31.

REF 24

Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies. J Med Chem. 1993 Apr 30;36(9):1136-45.

REF 25

Arylacetamide kappa opioid receptor agonists with reduced cytochrome P450 2D6 inhibitory activity. Bioorg Med Chem Lett. 2005 May 16;15(10):2647-52.

REF 26

Sesquiterpenes and flavonol glycosides from Zingiber aromaticum and their CYP3A4 and CYP2D6 inhibitory activities. J Nat Prod. 2004 Jul;67(7):1079-83.

REF 27

Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes. J Med Chem. 2003 Jul 17;46(15):3230-44.

REF 28

Pyrimidinylimidazole inhibitors of CSBP/p38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes. Bioorg Med Chem Lett. 1998 Nov 17;8(22):3111-6.

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