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

Abstract

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® proteins are GPCRs which have been minimally engineered to impart thermostability. StaRs® 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® 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_2AR) 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.