Using the β2-Adrenoceptor for Structure-Based Drug Design

The topics of molecular modeling and drug design are studied in a medicinal chemistry course. The recently reported structures of several G protein-coupled receptors (GPCR) with bound ligands have been used to develop a simple computer-based experiment employing molecular-modeling software. Knowledge of the specific interactions between a ligand (e.g., a drug) and the receptor allows an analysis of these contacts and enables the design of new ligands. We report a procedure to perform a thorough analysis of the binding site of the β2-adrenoceptor and identify the key interactions with the bound drug, carazolol. Armed with this information and a general knowledge of chemical functional groups, undergraduate students are able to suggest simple modifications to incorporate additional groups in the drug to better interact with the receptor. This computer-based experiment would also be appropriate for an organic or biochemistry course.