RT Journal Article
SR Electronic
T1 THREE-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS OF CYTOCHROMES P450: EFFECT OF INCORPORATING HIGHER-AFFINITY LIGANDS AND POTENTIAL NEW APPLICATIONS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 873
OP 878
DO 10.1124/dmd.105.004325
VO 33
IS 7
A1 Charles W. Locuson
A1 Jan L. Wahlstrom
YR 2005
UL http://dmd.aspetjournals.org/content/33/7/873.abstract
AB Recently, two new classes of reversible inhibitors, the benzbromarones (BZBRs) and the N-3 substituted phenobarbitals (PBs), were used to study the active site characteristics of CYP2C9 and 2C19, respectively. Since these ligands are some of the first CYP2C ligands to extend into the low nanomolar Ki range (Ki < 100 nM), they were subjected to three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis. Given that BZBRs 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 3D 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 3D-QSAR and molecular modeling techniques that may be useful in the study of cytochromes P450 specifically. The American Society for Pharmacology and Experimental Therapeutics