Molecular Dynamics Simulation of the Cytosolic AHR Complex with Indirubin or BAY2416964

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in metabolism, cell motility, development, and immune responses. Its dysregulation is linked to various diseases, including cancer, where it can enhance tumor progression and suppress immune responses. High-resolution cryo-electron microscopy (cryo-EM) structures of the human cytosolic AHR complex have become available and have provided insights into its agonist-binding mechanisms. However, understanding of AHR antagonist binding remains limited. Our computational study, using the structure of the indirubin-bound human AHR complex and diverse state-of-the-art docking algorithms and molecular dynamics simulations, suggests that AHR antagonists may bind either to the ligand-binding pocket or to alternative as yet unexplored sites outside of the ligand-binding pocket. This finding suggests novel molecular mechanisms of AHR inhibition that will advance our understanding of the therapeutic potential of current AHR inhibitors and support future drug development efforts.