Molecular Docking study of flavonoids to block the Aryl Hydrocarbon Receptor.

Anti-HIF flavonoids have been described with antitumor activities by interfering with a presumed antioxidant mechanism through direct and indirect ways of overexpression of Hypoxia Inducible Factor (HIF-1α). The aryl hydrocarbon receptor (AhR) is a protein homologous to HIF-1α and is overexpressed in smoking patients suffering from lung and breast cancer. The interaction of thirteen flavonoids group with the AhR was evaluated by molecular docking. The AhR:ARNT model obtained by SwissModel was used for docking with the MOE 2019.01 program, as well as several servers for the determination of protein-protein interactions and alanine mutations. For the blocking of AhR:functional ARNT different interaction sites were identified. The interface between the bHLH and PAS-A domains plays a major role between the sites. The blocking capacity to AhR:ARNT for flavonoids 4´,7-dihydroxy-flavone, fisetin, luteolin, flavone, apigenin, and galangin was around 50% to 60%. None of the flavonoids evaluated bound to the PAS-B domain (AhR active site). Only flavone and fisetin were found to be active to bind to ARNT at the level of the α-helical region in the PAS-A domain of this monomeric protein. All flavonoids studied bound to AhR (with the exception of flavone) and to ARNT (except for the compounds 3,7-dihydroxy-flavone and kaempferol). The best flavonoid for blocking the formation of the AhR:ARNT heterodimer was fisetin, which is found in food sources such as strawberries, apples, and grapes, and has shown the ability to reduce pro-cancer inflammatory markers in colorectal cancer patients.