@article {Afzelius909, author = {Lovisa Afzelius and Ismael Zamora and Marianne Ridderstr{\"o}m and Tommy B. Andersson and Anders Karl{\'e}n and Collen M. Masimirembwa}, title = {Competitive CYP2C9 Inhibitors: Enzyme Inhibition Studies, Protein Homology Modeling, and Three-Dimensional Quantitative Structure-Activity Relationship Analysis}, volume = {59}, number = {4}, pages = {909--919}, year = {2001}, doi = {10.1124/mol.59.4.909}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/59/4/909}, eprint = {https://molpharm.aspetjournals.org/content/59/4/909.full.pdf}, journal = {Molecular Pharmacology} }