Covalently-binding GPCR ligands: synthesis and biological investigation

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G protein-coupled receptors (GPCRs) belong to the most important pharmaceutical targets. Thus, more than 30 % of the approved drugs exert their biological activity upon binding to GPCRs. High-resolution X-ray crystal structures of GPCR ligand complexes substantially contribute to the understanding of their function and facilitate a structure-based design of novel candidate drugs based on its binding pocket rather than lead compounds. Developing covalently binding receptor ligands, we could contribute to recent GPCR crystal structures. In continuation of our collaboration with Prof. Brian Kobilka (Stanford University), we intend to develop novel covalent ligands addressing molecular determinants of subtype selectivity, the activation of Gq coupled receptors, the principle of functional selectivity, receptor dimerization and partial agonist effects. Moreover, we wish to develop covalent ligands that may serve as tools to discover new screening hits by using nanoswitch based technology (collaboration with Prof. Wesley Wong, Harvard University).