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Drug-Target Interaction

Drug

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PubChem ID:64143
Structure:
Synonyms:
(3S,4aS,8aS)-N-tert-butyl-2-[(2R,3R)-2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-phenylsulfanylbutyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-3-carboxamide
(3S-(2(2S*,3S*),3alpha,4abeta,8abeta))-N-(1,1-Dimethylethyl)decahydro-2-(2
(3S-(2(2S*,3S*),3alpha,4abeta,8abeta))-N-(1,1-Dimethylethyl)decahydro-2-(2-hydroxy-3-((3-hydroxy-2-methylbenzoyl)amino)-4-(phenylthio)butyl)-3-isoquinolinecarboxamide
159989-64-7
159989-65-8
159989-65-8 (MESYLATE SALT)
1ohr
1UN
2-[2-HYDROXY-3-(3-HYDROXY-2-METHYL-BENZOYLAMINO)-4-PHENYL SULFANYL-BUTYL]-DECAHYDRO-ISOQUINOLINE-3-CARBOXYLIC ACID TERT-BUTYLAMIDE
3-Isoquinolinecarboxamide, N-(1,1-dimethylethyl)decahydro-2- [(2R,3R)-2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-, (3S,4aS,8aS)-
3-Isoquinolinecarboxamide, N-(1,1-dimethylethyl)decahydro-2-((2R,3R)-2-hydroxy-3-((3-hydroxy-2-methylbenzoyl)amino)-4-(phenylthio)butyl)-, (3S,4aS,8aS)-
3-Isoquinolinecarboxamide, N-(1,1-dimethylethyl)decahydro-2-(2-hydroxy-3-((3-hydroxy-2-methylbenzoyl)amino)-4-(phenylthio)butyl)-, (3S-(2-(2S*,3S*),3-alpha,4a-beta,8a-beta))-
AG-1343
AG1343
AG1343 (*Mesylate salt*)
AG1346
AIDS-028590
AIDS-106820
AIDS028590
AIDS106820
C07257
C32H45N3O4S
DB00220
KS-1089
LS-85417
Met-SDF-1.beta. & Nelfinavir
Met-Stromal Cell-derived Factor-1.beta. (Human) & Nelfinavir
MLS001195634
MLS001304729
N-(1,1-Dimethylethyl)decahydro-2-(2-hydroxy-3-((3-hydroxy-2-methylbenzoyl)amino)-4-(phenylthio)butyl)-3-isoquinolinecarboxamide (3S-(2(2S*,3S*),3alpha,4abeta,8abeta))-
NCGC00090782-03
NCGC00090782-04
Nelfinavir
Nelfinavir mesylate
NELFINAVIR MESYLATE AG1343
Nelfinavir Monomethane Sulfonate
Nelfinavir [BAN:INN]
Nelfinavir [INN:BAN]
NFV
NLF
NSC722664 (MESYLATE SALT)
SMR000596515
STOCK6S-45709
Viracept
Viracept (*Mesylate salt*)
Viracept (TN)
VRX496
ATC-Codes:

Target

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Uniprot ID:CP3A5_HUMAN
Synonyms:
CYPIIIA5
Cytochrome P450 3A5
HLp2
P450-PCN3
EC-Numbers:1.14.14.1
Organism:Homo sapiens
Human
PDB IDs:-

Binding Affinities:

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

References:

15523003
Mechanism-based inactivation of CYP3A by HIV protease inhibitors.. C Steven Ernest2nd; Stephen D Hall; David R Jones (2005) The Journal of pharmacology and experimental therapeutics display abstract
Human immunodeficiency virus (HIV) protease inhibitors (PIs) are inhibitors of CYP3A enzymes, but the mechanism is poorly defined. In this study, time- and concentration-dependent decreases in activity as defined by maximum rate of inactivation (k(inact)) and inhibitor concentration that gives 50% maximal inactivation (K(I)) of CYP3A by amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir were quantified using testosterone 6beta-hydroxylation as a marker for CYP3A activity with recombinant CYP3A4(+b(5)), recombinant CYP3A5, and pooled human liver microsomes (HLMs). All the PIs, except indinavir, displayed inactivation with CYP3A4(+b(5)) and HLMs. Ritonavir was the most potent (K(I) = 0.10 and 0.17 microM) and demonstrated high k(inact) values (0.32 and 0.40 min(-1)) with both CYP3A4(+b(5)) and HLMs. Ritonavir was not significantly depleted by high-affinity binding with CYP3A4(+b(5)) and confirmed that estimation of reversible inhibition was confounded with irreversible inhibition. For CYP3A5, nelfinavir exhibited the highest k(inact) (0.47 min(-1)), but ritonavir was the most potent (K(I) = 0.12 microM). Saquinavir and indinavir did not show time- and concentration-dependent decreases in activity with CYP3A5. Spectrophototmetrically determined metabolic intermediate complex formation was observed for all of the PIs with CYP3A4(+b(5)), except for lopinavir and saquinavir. The addition of nucleophilic and free aldehyde trapping agents and free iron and reactive oxygen species scavengers did not prevent inactivation of CYP3A4(+b(5)) by ritonavir, amprenavir, or nelfinavir, but glutathione decreased the inactivation by saquinavir (17%) and catalase decreased the inactivation by lopinavir (39%). In conclusion, all the PIs exhibited mechanism-based inactivation, and predictions of the extent and time course of drug interactions with PIs could be underestimated if based solely on reversible inhibition.
16433896
Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro.. Marika T Granfors; Jun-Sheng Wang; Lauri I Kajosaari; Jouko Laitila; Pertti J Neuvonen; Janne T Backman (2006) Basic & clinical pharmacology & toxicology display abstract
The effects of five HIV protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir and saquinavir) on cytochrome P450 (CYP) 3A4, 3A5 and 3A7 activities were studied in vitro using testosterone 6beta-hydroxylation in recombinant CYP3A4, CYP3A5 and CYP3A7 enzymes. The protease inhibitors showed differential inhibitory effects on the three CYP3A forms. Ritonavir and saquinavir were non-selective and preferential inhibitors of CYP3A4 and CYP3A5 (K(i) 0.03 microM and 0.6-0.8 microM for ritonavir and saquinavir, respectively), and weaker inhibitors of CYP3A7 (K(i) 0.6 microM and 1.8 microM, respectively). Nelfinavir was a potent and non-selective inhibitor of all three CYP3A forms (K(i) 0.3-0.4 microM). Amprenavir and indinavir preferentially inhibited CYP3A4 (K(i) 0.1 microM and 0.2 microM, respectively), with weaker inhibitory effects on CYP3A5 (K(i) 0.5 microM and 2.2 microM, respectively) and CYP3A7 (K(i) 2.1 microM and 10.6 microM, respectively). In conclusion, significant differences exist in the inhibitory potency of protease inhibitors for different CYP3A forms. Ritonavir, nelfinavir, saquinavir and amprenavir seem to be prone to drug-drug interactions by inhibiting both CYP3A4 and CYP3A5. Especially nelfinavir and ritonavir also have a potential to inhibit foetal CYP3A7-mediated drug metabolism and some endogenous pathways that may be crucial to normal foetal development, while indinavir has the lowest potential to inhibit CYP3A5 and CYP3A7.
9616191
Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5: mechanism-based inactivation of cytochrome P4503A by ritonavir.. T Koudriakova; E Iatsimirskaia; I Utkin; E Gangl; P Vouros; E Storozhuk; D Orza; J Marinina; N Gerber (1998) Drug metabolism and disposition: the biological fate of chemicals display abstract
Both ritonavir and indinavir were readily metabolized by human intestinal microsomes. Comparison of the patterns of metabolites in incubations with enterocyte microsomes and expressed cytochrome P450 (CYP) isozymes and immunoinhibition and chemical inhibition studies showed the essential role of the CYP3A subfamily in the metabolism of both protease inhibitors by the small intestine. Ritonavir was similarly biotransformed by microsomes containing expressed CYP3A4 or CYP3A5 isozymes (KM = 0.05-0.07 microM, Vmax = 1-1.4 nmol/min/nmol CYP). In contrast, both the patterns of metabolites and the enzyme kinetic parameters for the metabolism of indinavir by expressed CYP3A5 (KM = 0.21 microM, Vmax = 0.24 nmol/min/nmol CYP) and CYP3A4 (KM = 0.04 microM, Vmax = 0.68 nmol/min/nmol CYP) were different. The biotransformation of both indinavir and ritonavir in human enterocyte microsomes was characterized by very low KM values (0.2-0.4 microM for indinavir and
SuperCyp