A Refined 3-Dimensional QSAR of Cytochrome P450 2C9:  Computational Predictions of Drug Interactions

• Published in: Journal of medicinal chemistry Vol. 43; no. 15; pp. 2789 - 2796
• Main Authors: Rao, Sreedhara, Aoyama, Ron, Schrag, Michael, Trager, William F, Rettie, Allan, Jones, Jeffrey P
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 27.07.2000
• Subjects: Aryl Hydrocarbon Hydroxylases; Binding Sites; Biological and medical sciences; Cytochrome P-450 Enzyme System - chemistry; Cytochrome P-450 Enzyme System - metabolism; Drug Interactions; Enzyme Inhibitors - chemistry; General pharmacology; Ligands; Medical sciences; Models, Biological; Models, Molecular; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Protein Binding; Reproducibility of Results; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases - chemistry; Steroid Hydroxylases - metabolism; Structure-Activity Relationship; Sulfaphenazole - chemistry; Sulfaphenazole - metabolism; Sulfonamides - chemistry; Sulfonamides - metabolism; Warfarin - chemistry; Warfarin - metabolism; Human; Sulfonamide; Enzyme; Isozyme; Coumarine derivatives; Cytochrome P450; Active site; Prediction; Enzyme inhibitor; Inhibitor enzyme complex; Modeling; Three dimensional model; Structure activity relation; Carboxylic acid; Sulfonylureas; Comparative molecular field analysis method; Drug-metabolizing enzyme; Electrostatic model
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000048n

A ligand-based model is reported that predicts the K i values for cytochrome P450 2C9 (CYP2C9) inhibitors. This CoMFA model was used to predict the affinity of 14 structurally diverse compounds not in the training set and appears to be robust. The mean error of the predictions is 6 μM. The experimentally measured K i values of the 14 compounds range from 0.1 to 48 μM. Leave-one-out cross-validated partial least-squares gives a q 2 value of between 0.6 and 0.8 for the various models which indicates internal consistency. Random assignment of biological data to structure leads to negative q 2 values. These models are useful in that they establish a pharmacophore for binding to CYP2C9 that can be tested with site-directed mutagenesis. These models can also be used to screen for potential drug interactions and to design compounds that will not bind to this enzyme with high affinity.