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Vol. 290, Issue 1, 429-438, July 1999

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

Sean Ekins1 , Gianpaolo Bravi2 , Shelly Binkley, Jennifer S. Gillespie, Barbara J. Ring, James H. Wikel and Steven A Wrighton

Department of Drug Disposition (S.E., S.B., J.S.G., B.J.R., S.A.W.) and Computational Chemistry and Molecular Structure Research (G.B., J.H.W.), Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana

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 Ki 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 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 Ki pharmacophores generated with Catalyst were also validated by predicting the Ki(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 Ki(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.

0022-3565/99/2901-0429$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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