Three- and four-dimensional-quantitative structure activity relationship (3D/4D-QSAR) analyses of CYP2C9 inhibitors

The interaction of competitive type inhibitors with the active site of cyto chrome P450 (CYP) 2C9 has been predicted using three- and four-dimensional quantitative structure activity relationship (3D-/4D-QSAR) models construct ed using previously unreported and literature-derived data. 3D-QSAR pharmac ophore models of the common structural features of CYP2C9 inhibitors were b uilt using the program Catalyst and compared with 3D- and 4D-QSAR partial l east-squares models, which use molecular surface-weighted holistic invarian t molecular descriptors of the size and shape of inhibitors. The Catalyst m odels generated from multiple conformers of competitive inhibitors of CYP2C 9 activities contained at least one hydrophobic and two hydrogen bond accep tor/donor regions. Catalyst model 1 was constructed with K-i(apparent) valu es for inhibitors of tolbutamide and diclofenac 4'-hydroxylation (n = 9). C atalyst model 2 was generated from literature K-i(apparent) values for (S)- warfarin 7-hydroxylation (n = 29), and Catalyst model 3 from literature IC5 0 values for tolbutamide 4-hydroxylation (n = 13). These three models illus trated correlation values of observed and predicted inhibition for CYP2C9 o f r = 0.91, 0.89, and 0.71, respectively. Catalyst pharmacophores generated with K-i(apparent) values were validated by predicting the K-i(apparent) v alue of a test set of CYP2C9 inhibitors also derived from the literature (n = 14). Twelve of fourteen of these K-i(apparent) values were predicted to be within 1 log residual of the observed value using Catalyst model 1, wher eas Catalyst model 2 predicted 10 of 14 K-i(apparent) values. The correspon ding partial least-squares molecular surface-weighted holistic invariant mo lecular 3D- and 4D-QSAR models for all CYP2C9 data sets yielded predictable models as assessed using cross-validation. These 3D- and 4D-QSAR models of CYP inhibition will aid in future prediction of drug-drug interactions.