RT Journal Article
SR Electronic
T1 Three- and Four-Dimensional Quantitative Structure Activity Relationship Analyses of Cytochrome P-450 3A4 Inhibitors
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 429
OP 438
VO 290
IS 1
A1 Sean Ekins
A1 Gianpaolo Bravi
A1 Shelly Binkley
A1 Jennifer S. Gillespie
A1 Barbara J. Ring
A1 James H. Wikel
A1 Steven A Wrighton
YR 1999
UL http://jpet.aspetjournals.org/content/290/1/429.abstract
AB 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 predictedKi 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 Ki values (n = 32) derived from the inhibition of CYP3A-mediated cyclosporin A metabolism and IC50 data (n = 22) from the inhibition of CYP3A4-mediated quinine 3-hydroxylation. These Catalyst pharmacophores illustrated correlations of observed and predicted inhibition for CYP3A4 ofr = 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. BothKi pharmacophores generated with Catalyst were also validated by predicting theKi(apparent) values of a test set of eight CYP3A4 inhibitors not included in either model. In seven of eight cases, the residuals of the predictedKi(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. The American Society for Pharmacology and Experimental Therapeutics