Characterization of type II ligands in CYP2C9 and CYP3A4.
Type II cytochrome P450 (CYP) ligands cause inhibition by direct coordination to the heme iron atom. This interaction usually leads to high inhibitory potential, which can cause drug-drug interaction. The approach to design compounds with diminished CYP inhibition is different depending on whether the compound binds (type II ligand) or not (type I ligand) to the iron atom of the heme group. In this study, the structural characteristics of nitrogen-containing compounds, which bind to the iron atom in two CYP isoforms (CYP2C9 and CYP3A4), were investigated. The in vitro assays applied were fluorescence inhibition assay, difference spectra measurements, and K s determination. Computational modeling as an alternative method to difference spectra measurements to distinguish between type I and type II ligands was also explored. Since two CYP isoforms were used, information about the isoform specificity of type II ligands was also analyzed. The in silico method developed in this study applied together with the information gained from the experimental measurements may result in better decisions during the drug discovery process.
Ahlström
Marie M
MM
Discovery DMPK and Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden. marie.m.ahlstrom@astrazeneca.com
Zamora
Ismael
I
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D001393:Azoles / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003198:Computer Simulation; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001393:Azoles; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D008024:Ligands; D011725:Pyridines; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human