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Drug-Target Interaction

Drug

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PubChem ID:3823
Structure:
Synonyms:
1-acetyl-4-(4-{[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazine
79156-75-5
CHEBI:48339
Fungarest
Fungoral
Ketoconazol
Ketoconazole
Ketoderm
KW 1414
NCI60_002728
NSC317629
Oprea1_683648
piperazine,
Side-Effects:
Side-EffectFrequency
abdominal pain0
nausea0
pain0
papilledema0
paresthesia0
pruritus0
swelling0
thrombocytopenia0
erythema0
urticaria0
vomiting0
chills0
photophobia0
pyogenic granuloma0
dry skin0
scalp seborrhea0
eye swelling0
acne0
leukopenia0
keratoconjunctivitis sicca0
alopecia0
anaphylaxis0
hemolytic anemia0
arrhythmia0
dermatitis0
contact dermatitis0
diarrhea0
dizziness0
somnolence0
rash0
fever0
gynecomastia0
headache0
hypersensitivity0
hypertriglyceridemia0
impetigo0
impotence0
allergic reaction0

Target

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Uniprot ID:CP2A6_HUMAN
Synonyms:
Coumarin 7-hydroxylase
CYP2A3
CYPIIA6
Cytochrome P450 2A6
P450 IIA3
P450(I)
EC-Numbers:1.14.14.1
Organism:Homo sapiens
Human
PDB IDs:1Z10 1Z11 2FDU 2FDV 2FDW 2FDY 3EBS
Structure:
3EBS

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----
----

References:

11978200
9143352
Inhibition of coumarin 7-hydroxylase activity in human liver microsomes.. A J Draper; A Madan; A Parkinson (1997) Archives of biochemistry and biophysics display abstract
Nine organic solvents and 47 commonly used P450 substrates and inhibitors were examined for their effects on coumarin 7-hydroxylase (CYP2A6) activity in human liver microsomes. Of the nine organic solvents examined (final concentration 1%, v/v), only methanol did not inhibit the 7-hydroxylation of coumarin (0.5 to 50 microM) by human liver microsomes. Dioxane and tetra-hydrofuran, which are structurally related to coumarin, were the most inhibitory solvents examined. Although the rates of coumarin 7-hydroxylation varied enormously among nine samples of human liver microsomes and cDNA-expressed CYP2A6 (Vmax = 179 to 2470 pmol/ mg protein/min), the Km for coumarin 7-hydroxylation was fairly constant (ranging from 0.50 to 0.70 microM). The following chemicals caused little or no inhibition of CYP2A6 as defined by a Ki > 200 microM: caffeine, chlorzoxazone, cimetidine, dextromethorphan, diazepam, diclofenac, erythromycin, ethinylestradiol, ethynyltestosterone, fluconazole, furafylline, furfural, hexobarbital, itraconazole, mephenytoin, methimazole, metronidazole, naringenin, naringin, nifedipine, norfloxacin, norgestrel, orphenadrine, quinidine, papaverine, phenacetin, pyrimethamine, ranitidine, spironolactone, sulfaphenazole, sulfinpyrazone, testosterone, tolbutamide, troleandomycin, and warfarin. In other words, these chemicals, at a final concentration of 100 microM, failed to inhibit CYP2A6 when the concentration of coumarin was equal to Km (0.50 microM). The following chemicals were classified as strong inhibitors of CYP2A6 (defined by Ki < 200 microM): clotrimazole, diethyldithiocarbamate, ellipticine, ketoconazole, 8-methoxypsoralen, 4-methylpyrazole, metyrapone, miconazole, alpha-naphthoflavone, nicotine, p-nitrophenol, and tranylcypromine. The potency with which each chemical inhibited the 7-hydroxylation of coumarin was independent of which sample of human liver microsomes was studied. One of the most potent inhibitors of coumarin 7-hydroxylase was 8-methoxypsoralen (methoxsalen), which was determined to be a mechanism-based inhibitor (suicide substrate) of CYP2A6 (k(inactivation) 0.5 min-1). With the exception of 8-methoxypsoralen, preincubation of human liver microsomes and NADPH with the aforementioned inhibitors did not increase their ability to inhibit CYP2A6. The most potent competitive inhibitor of CYP2A6 was tranylcypromine (Ki = 0.04 microM). Several of the chemicals that strongly inhibited CYP2A6, such as ketoconazole and tranylcypromine, are often used with the intention of selectively inhibiting human P450 enzymes other than CYP2A6. The results of this study underscore the need for a systematic evaluation of the specificity of commonly used P450 inhibitors.