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Issue 1, 2013
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Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A2A receptor

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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 A2A receptor (A2AR) 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.

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

  • This article is part of the themed collection: New Talent
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Publication details

The article was received on 25 Jun 2012, accepted on 06 Sep 2012, published on 11 Sep 2012 and first published online on 11 Sep 2012


Article type: Review Article
DOI: 10.1039/C2MD20164J
Citation: Med. Chem. Commun., 2013,4, 52-67
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    Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A2A receptor

    S. P. Andrews and B. Tehan, Med. Chem. Commun., 2013, 4, 52
    DOI: 10.1039/C2MD20164J

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