Crystal structures of the A2A adenosine receptor and their use in medicinal chemistry

Kenneth A Jacobson

doi:10.1186/2193-9616-1-22

Abstract

New insights into drug design are derived from the X-ray crystallographic structures of G protein-coupled receptors (GPCRs), and the adenosine receptors (ARs) are at the forefront of this effort. The 3D knowledge of receptor binding and activation promises to enable drug discovery for GPCRs in general, and specifically for the ARs. The predictability of modeling based on the X-ray structures of the A2AAR has been well demonstrated in the identification, design and modification of both known and novel AR agonists and antagonists. It is expected that structure-based design of drugs acting through ARs will provide new avenues to clinically useful agents.

Highlights

Main text and discussionWe are designing more potent and subtype-selective receptor ligands, based on an understanding of the molecular recognition in the binding site
New insights into drug design are derived from the X-ray crystallographic structures of G protein-coupled receptors (GPCRs) (Jacobson & Costanzi 2012), and adenosine receptors (ARs) are at the forefront of this effort (Jaakola et al 2008; Dore et al 2011; Xu et al 2011)
Few compounds that act at these two receptor families are approved for clinical use, the ARs serve as important test cases for structure-based ligand design for GPCRs in general

Summary

Introduction

Main text and discussion We are designing more potent and subtype-selective receptor ligands, based on an understanding of the molecular recognition in the binding site. A very high resolution structure of an antagonist-bound A2AAR (1.8 Å) was reported and shown to predict allosteric interactions at a site deeper than the orthosteric ligand binding region (Liu et al 2013; Gutiérrezde-Terán et al 2013).

Results

Conclusion