**Abstract**

The development of ligands capable of binding to the aryl hydrocarbon receptor (AhR) and hijacking its signaling pathway is of potential use for the design of novel agents against breast cancer. To guide the synthesis of new compounds and characterize their binding to the AhR, we employed homology modeling, ligand docking, and molecular dynamics simulations. As there is currently no crystallographic information available for the structure of the AhR's ligand-binding PAS-B domain, a homology model was developed. The location of the binding site was identified by scanning the model for concave areas and comparing them to known ligand-binding sites in proteins related to the AhR, such as the CLOCK:BMAL1 transcriptional activator complex and the hypoxia-inducible factor-2α (HIF-2α). Docking of several chlorinated phenylacrylonitriles was performed with the modeling suite MOE, identifying π-π stacking, hydrophobic, and van der Waals interactions as the driving forces for binding, an observation consistent with the hydrophobic nature of the site. Molecular dynamics simulations with one of the compounds for 100 ns verified the overall stability of a docking-predicted pose and revealed the presence of interacting water molecules in the vicinity of the ligand. Given the buried location of the ligand in the core of the receptor, this observation was somewhat unexpected, but it explained a slight shift of the ligand pose seen during the simulation.

**Keywords:** homology model, molecular dynamics, MOE, ligand-binding interactions, docking, breast cancer, aryl hydrocarbon receptor
