Identification of amino acids associated with the agonist and antagonist activities of flavonoids in the PAS-B cavity of the aryl hydrocarbon receptor using molecular docking modeling and artificial intelligence techniques.

The aryl hydrocarbon receptor (AHR) responds to hundreds of natural and chemical substances and plays a role in defense against chemical insults and bacterial infections, in the adaptive immune response, and in the development of pathological conditions ranging from inflammatory disorders to neoplasms. Numerous natural, endogenous, and synthetic AHR agonists and antagonists have been discovered—including flavonoids, which can act as selective AHR modulators. Therefore, molecular docking and artificial intelligence techniques were used to determine the interaction of flavonoids with the AHR and to identify the amino acid residues associated with AHR agonist or antagonist activities. Twenty-three flavonoids—secondary metabolites from medicinal plants—were investigated (17 with pure agonist activity and 6 pure antagonists). The crystallographic structure of the AHR (PDB: 7vnh) and the MOE 2019.01 program were used for molecular docking, modeling, and complex visualization. Random Forest (version 2) was used as an artificial intelligence tool for amino acid pattern models.  Conserved amino acid residues (Tyr, Phe, and His) were identified; given their conservation, they likely play specific roles within the PAS-B domain cavity of the Drosophila melanogaster AHR. The following amino acid residues could contribute to flavonoid binding: His275, Phe279, Met284, Tyr305, Tyr336, and His366. His275 and Tyr305 are associated with antagonist activity, whereas Met284, Tyr336, and His366 are associated with agonist activity. Phe279 is common to both agonist and antagonist activities of flavonoids at the AHR.