Competitive CYP2C9 inhibitors: Enzyme inhibition studies, protein homologymodeling, and three-dimensional quantitative structure-activity relationship analysis

This study describes the generation of a three-dimensional quantitative str ucture activity relationship (3D-QSAR) model for 29 structurally diverse, c ompetitive CYP2C9 inhibitors defined experimentally from an initial data se t of 73 compounds. In parallel, a homology model for CYP2C9 using the rabbi t CYP2C5 coordinates was built. For molecules with a known interaction mode with CYP2C9, this homology model, in combination with the docking program GOLD, was used to select conformers to use in the 3D-QSAR analysis. The rem aining molecules were docked, and the GRID interaction energies for all con formers proposed by GOLD were calculated. This was followed by a principal component analysis (PCA) of the GRID energies for all conformers of all com pounds. Based on the similarity in the PCA plot to the inhibitors with a kn own interaction mode, the conformer to be used in the 3D-QSAR analysis was selected. The compounds were randomly divided into two groups, the training data set (n = 21) to build the model and the external validation set (n = 8). The PLS (partial least-squares) analysis of the interaction energies ag ainst the K-i values generated a model with r(2) = 0.947 and a cross-valida tion of q(2) = 0.730. The model was able to predict the entire external dat a set within 0.5 log units of the experimental K-i values. The amino acids in the active site showed complementary features to the grid interaction en ergies in the 3D-QSAR model and were also in agreement with mutagenesis stu dies.