CHAPTER 5: Fragment Screening of G Protein-Coupled Receptors

Fragment screening and fragment-based drug discovery (FBDD) are still in their infancy for membrane-associated protein targets such as G protein-coupled receptors (GPCRs). However, with the advent of a new era of structural insight from X-ray crystal structures of multiple GPCRs and advances in the purification and isolation of these sensitive proteins, rapid progress is being made in the establishment, validation and practice of FBDD for this important class of drug targets. In this chapter the recent literature is reviewed, outlining key developments in the structural biology, biophysics and fragment-based screening of GPCRs. A case study of FBDD with the β₁ adrenergic receptor is described in some depth. Finally, a perspective on likely future developments is given.