Three- and Four-Dimensional Quantitative Structure Activity Relationship Analyses of Cytochrome P-450 3A4 Inhibitors

The program Catalyst was used to build three-dimensional quantitative structure activity relationship (3D-QSAR) pharmacophore models of the structural features common to competitive-type inhibitors of cytochrome P-450 (CYP) 3A4. These were compared with 3D- and four-dimensional (4D)-QSAR partial lea...

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Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 1999-07, Vol.290 (1), p.429-438
Main Authors: Ekins, S, Bravi, G, Binkley, S, Gillespie, J S, Ring, B J, Wikel, J H, Wrighton, S A
Format: Article
Language:English
Subjects:
Catalysis
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Hydroxylation
In Vitro Techniques
Kinetics
Liver - drug effects
Liver - enzymology
Microsomes, Liver - drug effects
Microsomes, Liver - enzymology
Midazolam - metabolism
Mixed Function Oxygenases - antagonists & inhibitors
Models, Molecular
Molecular Conformation
Structure-Activity Relationship
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Summary:The program Catalyst was used to build three-dimensional quantitative structure activity relationship (3D-QSAR) pharmacophore models of the structural features common to competitive-type inhibitors of cytochrome P-450 (CYP) 3A4. These were compared with 3D- and four-dimensional (4D)-QSAR partial least-squares (PLS) models built using molecular surface-weighted holistic invariant molecular (MS-WHIM) descriptors for size and shape of the inhibitor. The Catalyst pharmacophore model generated from multiple conformers of competitive inhibitors of CYP3A4-mediated midazolam 1′-hydroxylation ( n = 14) yielded a high correlation of observed and predicted K i values of r = 0.91. Similarly, PLS MS-WHIM was used to produce 3D- and 4D-QSARs for this data set and produced models that were statistically predictable after cross-validation. Two additional Catalyst pharmacophores were constructed from literature K i values ( n = 32) derived from the inhibition of CYP3A-mediated cyclosporin A metabolism and IC 50 data ( n = 22) from the inhibition of CYP3A4-mediated quinine 3-hydroxylation. These Catalyst pharmacophores illustrated correlations of observed and predicted inhibition for CYP3A4 of r = 0.77 and 0.92, respectively. The corresponding 4D-QSARs generated by PLS MS-WHIM for these data sets were of comparable quality as judged by cross-validation. Both K i pharmacophores generated with Catalyst were also validated by predicting the K i(apparent) values of a test set of eight CYP3A4 inhibitors not included in either model. In seven of eight cases, the residuals of the predicted K i(apparent) values were within 1 log unit of the observed values. The 3D- and 4D-QSAR models produced in this study suggest the utility of future in silico prediction of CYP3A4-mediated drug-drug interactions.
ISSN:0022-3565
1521-0103