In-depth analysis of the interactions of various aryl hydrocarbon receptor ligands from a computational perspective

Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that acts as a machinery that controls the expression of many genes, including cytochrome P450 CYP1A1, CYP1A2 and CYP1B1. It plays a principal role in numerous biological and toxicological functions, making it a promising target for developing therapeutic agents. Several novel small molecules targeting the AhR signaling pathway are currently under investigation as antitumor agents. Some have already advanced into clinical trials in patients with various tumors. Activation of AhR by diverse chemicals either endogenous or exogenous is initiated by the binding of these ligands to the PAS-B domain, which modulates AhR functions. There is, however, limited information about how various ligands interact with the PAS-B domain for activating or inhibiting the AhR. To better understand the mode of action of AhR agonists/antagonists. The current work proposes a combination of several computational tools to build dynamical models for the PAS-B domain bound to different ligands in mouse and human. Our findings reveal the essential roles of specific PAS-B residues (e.g., S365, V381& Q383), which mediate the AhR ligand-binding process. Our results also explain how these residues regulate the promiscuity of AhR in accommodating various chemicals in its binding PAS-B ligand-binding pocket.