Characterization of type II ligands in CYP2C9 and CYP3A4
Characterization of type II ligands in CYP2C9 and CYP3A4
复制标题
DOI：
10.1021/jm701121y
复制
发表时间：
2008-03-27
影响因子：
7.3
通讯作者：
Zamora, Ismael
中科院分区：
文献类型：
--
作者：
Ahlstrom, Marie M.;Zamora, Ismael
II型细胞色素P450 （CYP）配体通过与血红素铁原子的直接配位引起抑制。这种相互作用通常导致高抑制电位，从而引起药物-药物相互作用。设计CYP抑制减弱的化合物的方法取决于化合物是否与血红素基团的铁原子结合（II型配体）或不结合（I型配体）。本研究研究了CYP2C9和CYP3A4两种cypp亚型中与铁原子结合的含氮化合物的结构特征。体外实验采用荧光抑制法、差谱法和K-s法。计算建模作为差分光谱测量的替代方法来区分I型和II型配体也进行了探索。由于使用了两种CYP异构体，因此还分析了II型配体的异构体特异性信息。本研究中开发的计算机方法与从实验测量中获得的信息一起应用，可能会在药物发现过程中产生更好的决策。
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.