%0 Journal Article
%A Afzelius, Lovisa
%A Zamora, Ismael
%A RidderstrĂ¶m, Marianne
%A Andersson, Tommy B.
%A KarlĂ©n, Anders
%A Masimirembwa, Collen M.
%T Competitive CYP2C9 Inhibitors: Enzyme Inhibition Studies, Protein Homology Modeling, and Three-Dimensional Quantitative Structure-Activity Relationship Analysis
%D 2001
%R 10.1124/mol.59.4.909
%J Molecular Pharmacology
%P 909-919
%V 59
%N 4
%X This study describes the generation of a three-dimensional quantitative structure activity relationship (3D-QSAR) model for 29 structurally diverse, competitive CYP2C9 inhibitors defined experimentally from an initial data set of 73 compounds. In parallel, a homology model for CYP2C9 using the rabbit 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 remaining molecules were docked, and the GRID interaction energies for all conformers proposed by GOLD were calculated. This was followed by a principal component analysis (PCA) of the GRID energies for all conformers of all compounds. Based on the similarity in the PCA plot to the inhibitors with a known 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 against the K i values generated a model with r2 = 0.947 and a cross-validation of q2 = 0.730. The model was able to predict the entire external data set within 0.5 log units of the experimentalK i values. The amino acids in the active site showed complementary features to the grid interaction energies in the 3D-QSAR model and were also in agreement with mutagenesis studies.
%U http://molpharm.aspetjournals.org/content/molpharm/59/4/909.full.pdf