Theoretical quantitative structure–activity relationships of flavone ligands interacting with cytochrome P450 1A1 and 1A2 isozymes

Differential mechanisms for the inhibition of human cytochrome P450 1A2 by apigenin and genistein

“…These two solutions had the binding free energies of −8.50 kcal mol −1 in type 1 and −8.52 kcal mol −1 in type 2. In the both binding modes, the A ring of genistein was oriented to the heme iron of CYP1A2 (Figure 4) Among flavonoids examined in this study, galangin, kaempferol, chrysin, and apigenin were confirmed to be potent inhibitors of CYP1A2, as reported previously [5,6]. It is well known that the inhibitory effect of flavonoids on CYP isozymes is governed by the number of hydroxyl groups [5].…”

“…It has been reported that flavonoids have the ability to act as potent inhibitors for a variety of CYP enzymes. In particular, the ability of flavonoids to inhibit CYP1A2 has been extensively examined [5][6][7]. For instance, flavones such as chrysin and apigenin are potent inhibitors of CYP1A2 [5,6].…”

Comparative CYP1A1 and CYP1B1 substrate and inhibitor profile of dietary flavonoids

“…Flavonoid-binding to the catalytic domain of CYP1A1 and CYP1B1 has been investigated by a paucity of studies. Iori et al 22 examined the binding of flavonoids to the CYP1A1 and CYP1A2 active site using molecular modeling. Flavonoids carrying several hydroxyl groups, such as quercetin and myricetin were predicted to reside in close proximity to the heme site, leaving the catalytic site unperturbed.…”

“…In addition to EROD, several studies have employed molecular modeling analyzes to examine the flavonoid-inhibitor binding or substrate orientation of prototype ligands within the CYP1 enzyme active site. 21,22 In the present study we have examined the EROD-inhibitory activities of a range of hydroxylated and methoxylated flavonoids (Table 1) towards CYP1A1 and CYP1B1, as well as the metabolism of the monomethoxylated flavone acacetin and the poly-methoxylated flavone eupatorin-5-methyl ether by both enzymes. A homology model was further constructed using the CYP1A2 crystal structure as a template, and the binding mode of selected flavonoids to the heme group was investigated.…”

In Silico Modeling of P450 Substrates, Inhibitors, Activators, and Inducers

“…Energetic calculations from COMBINE and the results of GRID/GOLPE were consistent and identified regions of hydrophobic preference as well as hydrogen bonding. Iori et al (2005) [21] docked a set of 21 flavone structures into a homology model of CYP1A2 and computed CHARMM molecular mechanics interaction terms for the complexes. Quantum mechanical calculations on the isolated small molecules were also done, and both sets of descriptors investigated for their relationship with IC50 values for inhibition of CYP1A2 activity from three independent studies, necessitating division of the dataset into 3 subgroups.…”