Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A2A receptor

Significant progress has been made with stabilising G protein-coupled receptors (GPCRs) in recent years, and this has enabled the structures of several members of this important target class to be solved by X-ray crystallography. High resolution structural data is improving our understanding of GPCR activation and function, and is beginning to impact the drug discovery community. StaR (R) proteins are GPCRs which have been minimally engineered to impart thermostability. StaRs (R) are stable in detergent micelles and are suitable reagents for use with X-ray crystallography, biophysical screening techniques and fragment screening. This article reviews the role that StaRs (R) can play in the identification and optimisation of novel ligands for GPCRs by examining a specific case in which a preclinical candidate for the treatment of Parkinson's disease was developed. Compound 13 was identified following the virtual screening of experimentally enabled homology models of adenosine A(2A) receptor (A(2A)R) and was subsequently optimised using the structural insight provided by X-ray crystallography and Biophysical Mapping of closely related molecules. Compound 19 is an exemplar from this chemical series which displays low molecular weight and high oral bioavailability; it has a good pharmacokinetic profile and is highly efficacious in preclinical models of Parkinson's disease.