Target Information

Target General Information

Target ID

T37848 (Former ID: TTDS00418)

Target Name

Albendazole monooxygenase (CYP3A4)

Synonyms

Taurochenodeoxycholate 6-alpha-hydroxylase; Quinine 3-monooxygenase; P450-PCN1; Nifedipine oxidase; NF-25; HLp; Cytochrome P450-PCN1; Cytochrome P450 NF-25; Cytochrome P450 HLp; Cytochrome P450 3A4; Cytochrome P450 3A3; CYPIIIA4; CYPIIIA3; CYP3A3; Albendazole sulfoxidase; Albendazole monooxygenase (sulfoxide-forming); 1,8-cineole 2-exo-monooxygenase

Gene Name

CYP3A4

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Function

In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e. g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide. Catalyzes 4-beta-hydroxylation of cholesterol. May catalyze 25-hydroxylation of cholesterol in vitro. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole. Cytochromes P450 are a group of heme-thiolate monooxygenases.

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BioChemical Class

Paired donor oxygen oxidoreductase

UniProt ID

CP3A4_HUMAN

EC Number

EC 1.14.14.-

Sequence

MALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMF
DMECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISI
AEDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYS
MDVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICV
FPREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSI
IFIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVV
NETLRLFPIAMRLERVCKKDVEINGMFIPKGVVVMIPSYALHRDPKYWTEPEKFLPERFS
KKNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLG
GLLQPEKPVVLKVESRDGTVSGA

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3D Structure

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PDB

ADReCS ID

BADD_A00232 ; BADD_A00376 ; BADD_A00541 ; BADD_A00659 ; BADD_A01336 ; BADD_A01965 ; BADD_A02053 ; BADD_A02189 ; BADD_A02216 ; BADD_A02978 ; BADD_A03877 ; BADD_A04155 ; BADD_A04220 ; BADD_A04253 ; BADD_A04263 ; BADD_A04424 ; BADD_A05280 ; BADD_A05957 ; BADD_A05962 ; BADD_A06627

HIT2.0 ID

T85AXP

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

Curcumin

Drug Info

Phase 3

Solid tumour/cancer

[2], [3]

PMX-53

Drug Info

Phase 2

Atopic dermatitis

[4], [5]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 66 Inhibitor drugs

Curcumin

Drug Info

[1]

PMX-53

Drug Info

[6]

(-)-clusin

Drug Info

[7]

(-)-cubebin

Drug Info

[7]

(-)-cubebinin

Drug Info

[7]

(-)-cubebininolide

Drug Info

[7]

(-)-dihydroclusin

Drug Info

[7]

(-)-thujaplicatintrimethyl ether

Drug Info

[7]

(-)-yatein

Drug Info

[7]

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

Drug Info

[8]

(8R,8'R)-4-hydroxycubebinone

Drug Info

[7]

(8R,8'R,9'S)-5-methoxyclusin

Drug Info

[7]

1,1':4',1''-terphenyl-3,3''-diol

Drug Info

[9]

1,2-Diacetoxylycorine

Drug Info

[10]

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

Drug Info

[11]

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

Drug Info

[12]

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

Drug Info

[11]

1-Acetoxy-2-tert-butyldimethylsilyl-oxylycorine

Drug Info

[10]

1-Acetoxylycorine

Drug Info

[10]

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

Drug Info

[13]

2,5-bis(4-hydroxybenzylidene)cyclopentanone

Drug Info

[1]

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

Drug Info

[14]

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

Drug Info

[12]

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

Drug Info

[15]

2-fluoro-5-(3-methylthiophen-2-yl)pyridine

Drug Info

[8]

2-tert-Butyldimethylsilyloxylycorine

Drug Info

[10]

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

Drug Info

[12]

3,3-(1,3-Thiazole-2,5-diyl)diphenol

Drug Info

[9]

3-(3-methylthiophen-2-yl)pyridine

Drug Info

[8]

3-(5-((methylthio)methyl)furan-2-yl)pyridine

Drug Info

[8]

3-(5-[1,3]dithiolan-2-yl-furan-2-yl)pyridine

Drug Info

[8]

3-(pyridin-3-yl)prop-2-yn-1-amine

Drug Info

[8]

3-methoxy-5-(6-methoxynaphthalen-2-yl)pyridine

Drug Info

[16]

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

Drug Info

[12]

3-[3-(4-Methoxybenzyl)naphthalen-2-yl]pyridine

Drug Info

[17]

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

Drug Info

[9]

4-(6-Methoxynaphthalen-2-yl)isoquinoline

Drug Info

[16]

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

Drug Info

[12]

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

Drug Info

[12]

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

Drug Info

[15]

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

Drug Info

[15]

5-(2-phenethylpiperazin-1-yl)-1H-indazole

Drug Info

[18]

5-Pyridin-3-yl-thiophene-2-carbaldehyde oxime

Drug Info

[19]

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

Drug Info

[11]

6-(3-Hydroxy-phenyl)-naphthalen-2-ol

Drug Info

[20]

6-Pyridin-3-yl-3,4-dihydronaphthalen-2(1H)-one

Drug Info

[21]

Alpha-Hydroxy-Midazolam

Drug Info

[22]

Alpha-methylcubebin

Drug Info

[7]

BERGAPTOL

Drug Info

[23]

BMS-536924

Drug Info

[24]

DIETHOXYFLOURESCEIN

Drug Info

[25]

DIHYDROCUBEBIN

Drug Info

[7]

ETHOXYCLUSIN

Drug Info

[7]

Geranylcoumarin

Drug Info

[23]

Go-Y026

Drug Info

[1]

GSK-8062

Drug Info

[26]

Heme

Drug Info

[27]

HINOKININ

Drug Info

[7]

JATRORRHIZINE

Drug Info

[28]

MEDIORESINOL

Drug Info

[7]

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

Drug Info

[19]

ML-3163

Drug Info

[29]

ML-3375

Drug Info

[29]

ML-3403

Drug Info

[29]

PALMATINE

Drug Info

[28]

TILIROSIDE

Drug Info

[30]

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

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 9 KEGG Pathways	+
1	Steroid hormone biosynthesis
2	Linoleic acid metabolism
3	Retinol metabolism
4	Metabolism of xenobiotics by cytochrome P450
5	Drug metabolism - cytochrome P450
6	Drug metabolism - other enzymes
7	Metabolic pathways
8	Bile secretion
9	Chemical carcinogenesis
Pathwhiz Pathway	[+] 2 Pathwhiz Pathways	+
1	Caffeine Metabolism
2	Retinol Metabolism
Reactome	[+] 2 Reactome Pathways	+
1	Xenobiotics
2	Aflatoxin activation and detoxification
WikiPathways	[+] 19 WikiPathways	+
1	Metapathway biotransformation
2	Aflatoxin B1 metabolism
3	Estrogen metabolism
4	Benzo(a)pyrene metabolism
5	Tamoxifen metabolism
6	Tryptophan metabolism
7	Oxidation by Cytochrome P450
8	Nuclear Receptors in Lipid Metabolism and Toxicity
9	Nuclear Receptors Meta-Pathway
10	Farnesoid X Receptor Pathway
11	Vitamin D Receptor Pathway
12	Felbamate Metabolism
13	Lidocaine metabolism
14	Nifedipine Activity
15	Colchicine Metabolic Pathway
16	Irinotecan Pathway
17	Drug Induction of Bile Acid Pathway
18	Fatty Acid Omega Oxidation
19	Codeine and Morphine Metabolism

Target-Related Models and Studies

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Target Validation

Target Validation Info

Target QSAR Model

References

Top

REF 1

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 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: 7000).

REF 3

Nanocurcumin: a promising therapeutic advancement over native curcumin. Crit Rev Ther Drug Carrier Syst. 2013;30(4):331-68.

REF 4

REF 5

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 6

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 7

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

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

Design, synthesis, biological evaluation and pharmacokinetics of bis(hydroxyphenyl) substituted azoles, thiophenes, benzenes, and aza-benzenes as p... J Med Chem. 2008 Nov 13;51(21):6725-39.

REF 10

Selective cytochrome P450 3A4 inhibitory activity of Amaryllidaceae alkaloids. Bioorg Med Chem Lett. 2009 Jun 15;19(12):3233-7.

REF 11

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 12

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

REF 13

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 14

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 15

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 16

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 17

Novel aldosterone synthase inhibitors with extended carbocyclic skeleton by a combined ligand-based and structure-based drug design approach. J Med Chem. 2008 Oct 9;51(19):6138-49.

REF 18

2-Substituted N-aryl piperazines as novel triple reuptake inhibitors for the treatment of depression, Bioorg. Med. Chem. Lett. 20(13):3941-3945 (2010).

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

Design, synthesis, and biological evaluation of (hydroxyphenyl)naphthalene and -quinoline derivatives: potent and selective nonsteroidal inhibitors... J Med Chem. 2008 Apr 10;51(7):2158-69.

REF 21

In vivo active aldosterone synthase inhibitors with improved selectivity: lead optimization providing a series of pyridine substituted 3,4-dihydro-... J Med Chem. 2008 Dec 25;51(24):8077-87.

REF 22

Design and synthesis of a new fluorescent probe for cytochrome P450 3A4 (CYP 3A4). Bioorg Med Chem Lett. 2003 Nov 3;13(21):3643-5.

REF 23

Radical scavenging and cytochrome P450 3A4 inhibitory activity of bergaptol and geranylcoumarin from grapefruit. Bioorg Med Chem. 2007 Jun 1;15(11):3684-91.

REF 24

Discovery and evaluation of 4-(2-(4-chloro-1H-pyrazol-1-yl)ethylamino)-3-(6-(1-(3-fluoropropyl)piperidin-4-yl)-4-methyl-1H-benzo[d]imidazol-2-yl)py... J Med Chem. 2008 Oct 9;51(19):5897-900.

REF 25

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 26

Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064. Bioorg Med Chem Lett. 2008 Aug 1;18(15):4339-43.

REF 27

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 28

Cytochrome P3A4 inhibitors and other constituents of Fibraurea tinctoria. J Nat Prod. 2007 Dec;70(12):1930-3.

REF 29

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 30

Isolation of cytochrome P450 inhibitors from strawberry fruit, Fragaria ananassa. J Nat Prod. 2004 Nov;67(11):1839-41.

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