Received for publication February 17, 2005.
Revised April 13, 2005.
Accepted for publication April 14, 2005.

3D-QSAR analysis of CYPs: Effect of incorporating higher affinity ligands and potential new applications

Abstract

Recently two new classes of reversible inhibitors, the benzbromarones (BZBR) and the N-3 substituted phenobarbitals (PB), were used to study the active site characteristics of CYPs 2C9 and 2C19, respectively. Since these ligands are some of the first CYP2C ligands to extend into the low nanomolar K_i range (K_i < 100 nM), they were subjected to three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis. Given that BZBR or the PB ligands bind very tightly it can be assumed that these structures complement the binding pocket(s) for these enzymes. Thus, the resulting models should output a 3-D arrangement of interaction sites predicted to be important for near optimal binding to the CYP2C9 and CYP2C19 enzymes. These predicted interaction regions may then improve the ability to predict drug-drug interactions. The resulting models generated from these new high affinity ligands are discussed, as are novel uses of 3-D QSAR and molecular modeling techniques that may be useful in the study of CYPs specifically.

Key words: computational models, CYP2C, cytochrome P450, inhibition, structure-activity relationships