HOMOLOGY MODELING OF ARYL HYDROCARBON RECEPTOR AND DOCKING OF AGONISTS AND ANTAGONISTS

摘要

The aryl hydrocarbon receptor (Ah receptor or AhR) is a nuclear receptor, located in the cytoplasm. Bec ause of its association with carcinogenicity, the AhR has become a critical receptor for identifying the unknown endocrine disruptors. The experimental 3D structure of the receptor is not available. This calls for the creation of the homology model of the Ligand-binding Domain (LBD) for the purpose of application of the structure-based methods. High affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domain was used as a template for the development of Homology model. The generated model was evaluated stereochemically and validated further by docking a set of known agonists and antagonists into the modeled LBD of mouse AhR. An attempt has been made to explain the observed experimental binding affinities and the site-directed mutagenesis data as reported in the literature with the results of docking. The results of docking of antagonists indicate that these form distinct H -bonds with the receptor as against the agonists where hydrophobic interactions have predominated. The model can be used for the screening of ligands for AhR binding activity