Molecular docking of retinoic acid with cytochrome P450 isoforms CYP1A1, 1A2 and 1B1 – a potential drug target against carcinogen benzo(a)pyrene

Abstract

Human cytochromes present in lungs, plays an important role in the metabolic activation of chemical carcinogens, and in particular, is thought to be linked to lung cancer. The mechanism of carcinogenesis is related to the enzyme's ability to oxidize highly toxic compounds, such as polycyclic aromatic hydrocarbons (PAHs), to their carcinogenic derivatives. In order to better understand Cytochrome P450 (CYP) function, a homology model of this enzyme has been constructed with its isoforms CYP 1A1, CYP 1A2, and CYP 1B1. CYP substrates, such as benzo[a]pyrene [B(a)P], benzo[a]pyrene 7,8 dihydrodiol [B(a)P diol]  and Retinoic acid (RA)  were docked into the active site of the model, binding interactions and key amino acid residues able to interact with the substrate, have been identified. The analysis of enzyme-substrate interactions indicated that Vander wails, hydrogen and hydrophobic interactions are mainly responsible for binding of these substrates in the active site. CYP 1A1 and 1A2 shows the binding similarities comparing with CYP1B1. Key residues Ala and Gly in the position 317 and 318 play an important role both in procarcinogen activation and RA binding. Additionally, the binding free energy calculations were performed for the three substrates. Lower binding energy required for RA binding than procarcinogen activation. The obtained values were similar to those observed experimentally, which suggests that this approach might be useful for prediction of binding constants.