Abstract

G protein-coupled receptors (GPCRs) are an important and long-standing family of drug targets. Despite many historical success stories, today there are still a significant number of GPCRs with compelling pre-clinical validation that remain highly challenging for drug discovery.

Over the last 10 years there has been great progress in the structural biology of GPCRs facilitating Structure-Based Drug Design (SBDD) approaches. Sosei Heptares uses its proprietary StaR® technology to thermostabilise GPCRs by mutagenesis into a chosen conformational state. These purified proteins can then be used for biophysical screening techniques and crystallisation to yield X-ray structures with multiple ligands.

This presentation will illustrate how at Sosei Heptares we use our StaR® approach for GPCR structure and hit identification. A series of short case studies will review how we have used the structural identification of orthosteric and allosteric binding sites for SBDD and highlight how this approach has provided differentiated series over empirical methods.