Recent technological advances in the field of membrane protein structural biology have led to significantly improved success rates in the structure resolution of G protein-coupled receptors. Apart from gaining insight into the mechanics of receptor biology, these technical advances facilitate the application of structure-based drug discovery to G protein-coupled receptors. Structure-based drug discovery has the potential to significantly increase the efficiency and success rate of drug discovery campaigns against this important family of drug targets. Recently, structures of mGlu1 and mGlu5 transmembrane domains were reported in complex with negative allosteric modulators. Analysis of these structures reveals a fascinating insight into the historical difficulties associated with the drug discovery efforts for these receptors and provides an important novel template for structure-based drug discovery approaches to identify more diverse and better quality chemotypes.
Keywords: G protein-coupled receptor; allosteric modulators; mGlu5; mavoglurant; metabotropic glutamate receptor; structure based drug design.