Multifaceted Roles of Crystallography in Modern Drug Discovery

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 (Doré et al., Structure 19(9):1283–1293, 2011; Doré et al., Nature 511:557–562, 2014; Hollenstein et al., Nature 499(7459):438–443, 2013). A description of the StaR engineering approach, with several examples of how it has been applied, will be presented here. Three examples of how the StaR technology has impacted drug design are outlined. Firstly, X-ray structures of the adenosine A2AR StaR in the antagonist conformation have allowed identification of a clinical candidate progressing into phase 1 clinical trials for the treatment of attention deficit hyperactivity disorder (ADHD) and with potential for the treatment M. Congreve ( ) • A.S. Doré • A. Jazayeri • R. Nonoo Heptares Therapeutics Ltd., Biopark, Welwyn Garden City, UK e-mail: miles.congreve@heptares.com © Springer Science+Business Media Dordrecht 2015 G. Scapin et al. (eds.), Multifaceted Roles of Crystallography in Modern Drug Discovery, NATO Science for Peace and Security Series A: Chemistry and Biology, DOI 10.1007/978-94-017-9719-1_1 1 2 M. Congreve et al. of Parkinson’s disease. Secondly, the first Class B GPCR to be crystallized with a small molecule antagonist ligand, Corticotropin-releasing factor 1 (CRF1R) is presented. Finally, a Class C GPCR, metabotropic glutamate receptor 5 (mGlu5) has been crystallised with a negative allosteric modulator (NAM). Again in this case fragment and structure based drug design has been used to identify a pre-clinical candidate for the potential treatment of a range of CNS disorders.