Engineering G Protein-Coupled Receptors for Drug Design

G protein-coupled receptors (GPCRs) play a crucial role in many diseases and are the site of action of 25–30 % of current drugs (Overington et al., Nat Rev Drug Discov 5(12):993–996, 2006). As such GPCRs represent a major area of interest for the pharmaceutical industry. Despite the rich history of this target class there remain many opportunities for clinical intervention and there is a scarcity of high quality drug-like molecules for many receptors. High-throughput screening has often failed to unlock the potential of members of this superfamily and new, complementary approaches to GPCR drug discovery are required. However, the instability of GPCRs when removed from the cell membrane has severely limited the application of the techniques of structure-based and fragment-based drug discovery. The Heptares approach is successfully overcoming this fundamental challenge and facilitates both biophysical and biochemical fragment screening and also the generation of structural information. Heptares uses its StaR® technology to thermostabilise GPCRs using mutations in precisely defined biologically-relevant conformations (Robertson et al., Neuropharmacology 60(1):36–44, 2011). StaR proteins are amenable to techniques that cannot be readily used with wild-type GPCRs, including fragment screening, biophysical kinetic profiling and X-ray crystallography. Crystal structures of multiple GPCRs have been solved using this approach in the last 5 years (Dore et al., Structure 19(9):1283–1293, 2011; Dore et al., Nature 511:557–562, 2014; Hollenstein et al., Nature 499(7459):438–443, 2013).