Molecular Docking Study of Flavonoids to Block the Aryl Hydrocarbon Receptor

Abstract

Anti-HIF flavonoids have been described for their antitumor activity by interfering with a presumed antioxidant mechanism through direct and indirect ways of overexpression of the 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 with the AhR has been evaluated by molecular docking. The AhR:ARNT model obtained by SwissModel has been used for docking with the MOE 2019.01 program, as well as several servers for the determination of protein–protein interactions and alanine mutations. Different interaction sites were identified for blocking the AhR: functional ARNT, the interface between the bHLH and PAS-A domains, being important. The blocking capacity to AhR:ARNT proved to be between 50 and 60% for flavonoids 4′,7-dihydroxy-flavone, fisetin, luteolin, 5-hydroxy-2-(4′-hydroxy)-7-methoxy-flavonone, flavone, apigenin, galangin and 7-hydroxy-5-methoxy-flavonone. None of the flavonoids evaluated interact with the PAS-B domain (AhR active site). All the studied flavonoids interact with AhR, except flavone, and with ARNT except the compounds 3,7-dihydroxy-flavone and kaempferol. The best flavonoid for blocking the formation of the AhR:ARNT heterodimer proved to be 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 and lung cancer.

Keywords

• flavonoids
• molecular docking
• aryl hydrocarbon receptor