High-throughput screening for allosteric modulators of GPCRs

Abstract

The continued evolution of our understanding of G protein-coupled receptor (GPCR) signaling has revealed new opportunities for drug discovery. Specifi cally, biased agonism at GPCRs and allosteric modulation of GPCRs both represent emerging areas of GPCR biology that hold promise for the development of novel GPCR-targeted therapeutics that may provide greater therapeutic effi cacy and/or improved sideeffect profi les. To obtain initial chemical leads, high-throughput screening (HTS) of a large compound library for the desired activity is often deployed during the early stages of a discovery program. The identifi cation of allosteric modulators, in particular, poses signifi cant challenges for HTS. We describe several HTS protocols designed for the identifi cation of GPCR ligands, with a particular focus on the identifi cation of allosteric modulators.