G protein-coupled receptors (GPCRs) are a valuable family of drug targets but a significant number with compelling pre-clinical or clinical validation remain highly challenging for drug discovery. A key issue is their instability when solubilised away from the membrane, which results in them being difficult to crystallise and solve their X-ray structures. Heptares uses its proprietary StaR® technology to thermostabilise GPCRs by mutagenesis into a chosen conformational state. The purified proteins can then be used for biophysical screening techniques and crystallisation to yield X-ray structures with multiple ligands. Using the StaR® approach, Heptares has solved structures of multiple Class B GPCRs, leading to the identification of novel, allosteric, binding sites. The orthosteric binding sites of this class of receptors are typically open, mostly occupied by bulk-like solvent, and are therefore challenging from a SBDD perspective. In contrast, allosteric ligands bind in smaller, more closed sites with both hydrophobic and hydrophilic regions, making them more tractable for small molecule drug discovery. In this sense parallels can be drawn with Class C GPCRs such as the metabotropic glutamate receptor sub-family, where discovery of allosteric ligands is more tractable than targeting the large extracellular orthosteric glutamate binding site. The recently solved structures highlight the range of GPCR binding sites that are now known, and reveal a much greater diversity of ligand binding modes and positions than previously expected. Details of the allosteric binding sites of the CRF1 and glucagon receptors, insights into their druggability and implications for wider Class B targets, and how the structural information is being leveraged in a structure-based drug discovery campaign for the GLP-1 receptor will be presented.

Identification and exploitation of diverse GPCR allosteric small-molecule binding sites

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.