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Abstract
PurposeA2B receptor agonists are studied as possible therapeutic tools for a variety of pathological conditions. Unfortunately, medicinal chemistry efforts have led to the development of a limited number of potent agonists of this receptor, in most cases with a low or no selectivity versus the other adenosine receptor subtypes. Among the developed molecules, two structural families of compounds have been identified based on nucleoside and non-nucleoside (pyridine) scaffolds. The aim of this work is to analyse the binding mode of these molecules at 3D models of the human A2B receptor to identify possible common interaction features and the key receptor residues involved in ligand interaction.MethodsThe A2B receptor models are built by using two recently published crystal structures of the human A2A receptor in complex with two different agonists. The developed models are used as targets for molecular docking studies of nucleoside and non-nucleoside agonists. The generated docking conformations are subjected to energy minimization and rescoring by using three different scoring functions. Further analysis of top-score conformations are performed with a tool evaluating the interaction energy between the ligand and the binding site residues.ResultsResults suggest a set of common interaction points between the two structural families of agonists and the receptor binding site, as evidenced by the superimposition of docking conformations and by analysis of interaction energy with the receptor residues.ConclusionsThe obtained results show that there is a conserved pattern of interaction between the A2B receptor and its agonists. These information and can provide useful data to support the design and the development of A2B receptor agonists belonging to nucleoside or non-nucleoside structural families.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-9616-1-24) contains supplementary material, which is available to authorized users.
Highlights
Adenosine (Ado, Figure 1) is a naturally occurring nucleoside that mediates numerous physiological and pathological processes with effects on heart rate and atrial contractility, vascular smooth muscle tone, release of neurotransmitters, lipolysis, as well as renal, platelet, and white blood cell functions (Cristalli and Volpini 2003)
These information and can provide useful data to support the design and the development of A2B receptor agonists belonging to nucleoside or non-nucleoside structural families
To simulate the binding mode of nucleoside and nonnucleoside agonists at A2BAR and to compare the key ligand-target interaction features of the two structural families of compounds, a molecular docking analysis was performed at homology models of the human A2BAR developed by using two recently published crystal structures of the agonist-bound A2AAR as templates (pdb code: 2YDO; 3.0-Å resolution (Lebon et al 2011) and pdb code: 3QAK; 2.7-Å resolution (Xu et al 2011), in complex with Ado and UK-432097, respectively)
Summary
Adenosine (Ado, Figure 1) is a naturally occurring nucleoside that mediates numerous physiological and pathological processes with effects on heart rate and atrial contractility, vascular smooth muscle tone, release of neurotransmitters, lipolysis, as well as renal, platelet, and white blood cell functions (Cristalli and Volpini 2003). ARs can be distinguished on the basis of their tissue distribution and unique pharmacological profiles These membrane proteins, belonging to the G protein-coupled receptor (GPCR) family, are hot targets due to their therapeutic potential even though the lack of potent and selective ligands for all subtypes still represents a weakness for the attribution of specific biological activity and for the development of therapeutic tools. The A2BAR is widely expressed in the human body and regulates several biological events at cardiovascular, muscular, and central nervous systems, and in cell growth and during inflammation (Feoktistov and Biaggioni 1997) This receptor is of therapeutic interest for its targeting in several conditions (Baraldi et al 2009). Even the use of A2BAR agonists for the treatment of renal diseases, hypertension, cystic fibrosis, diabetes, and pulmonary diseases associated with hyperplasia has been considered (Volpini et al 2003; Dubey et al 2005)
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