Biophysical mapping of the adenosine A2A receptor.

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Zhukov A, Andrews SP, Errey JC, Robertson N, Tehan B, Mason JS, Marshall FH, Weir M, Congreve M

Biophysical mapping of the adenosine A2A receptor.

J Med Chem. 2011 Jul 14;54(13):4312-23. doi: 10.1021/jm2003798. Epub 2011 Jun 10.

PubMed ID

21661720 [ View in PubMed

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Abstract

A new approach to generating information on ligand receptor interactions within the binding pocket of G protein-coupled receptors has been developed, called Biophysical Mapping (BPM). Starting from a stabilized receptor (StaR), minimally engineered for thermostability, additional single mutations are then added at positions that could be involved in small molecule interactions. The StaR and a panel of binding site mutants are captured onto Biacore chips to enable characterization of the binding of small molecule ligands using surface plasmon resonance (SPR) measurement. A matrix of binding data for a set of ligands versus each active site mutation is then generated, providing specific affinity and kinetic information (K(D), k(on), and k(off)) of receptor-ligand interactions. This data set, in combination with molecular modeling and docking, is used to map the small molecule binding site for each class of compounds. Taken together, the many constraints provided by these data identify key protein-ligand interactions and allow the shape of the site to be refined to produce a high quality three-dimensional picture of ligand binding, thereby facilitating structure based drug design. Results of biophysical mapping of the adenosine A(2A) receptor are presented.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
4-{2-[(7-amino-2-furan-2-yl[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino]ethyl}phenol	Adenosine receptor A2a	Ki (nM)	2	N/A	N/A	Details
Caffeine	Adenosine receptor A2a	Ki (nM)	5011.87	N/A	N/A	Details
Theophylline	Adenosine receptor A2a	Ki (nM)	>10000	N/A	N/A	Details