Studies on 16 α -Hydroxylation of Steroid Molecules and Regioselective Binding Mode in Homology-Modeled Cytochrome P450-2C11

Abstract

We investigated the 16 α -hydroxylation of steroid molecules and regioselective binding mode in homology-modeled cytochrome P450-2C11 to correlate the biological study with the computational molecular modeling. It revealed that there was a positive relationship between the observed inhibitory potencies and the binding free energies. Docking of steroid molecules into this homology-modeled CYP2C11 indicated that 16 α -hydroxylation is favored with steroidal molecules possessing the following components, (1) a bent A-B ring configuration (5 β -reduced), (2) C-3 α -hydroxyl group, (3) C-17 β -acetyl group, and (4) methyl group at both the C-18 and C-19. These respective steroid components requirements were defined as the inhibitory contribution factor. Overall studies of the male rat CYP2C11 metabolism revealed that the above-mentioned steroid components requirements were essential to induce an effective inhibition of [ 3 H]progesterone 16 α -hydroxylation. As far as docking of homology-modeled CYP2C11 against investigated steroids is concerned, they are docked at the active site superimposed with flurbiprofen. It was also found that the distance between heme iron and C16 α -H was between 4 to 6 Å and that the related angle was in the range of 180 ± 45 ∘ .