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Simulation and comparative analysis of binding modes of nucleoside and non-nucleoside agonists at the A2B adenosine receptor.

Dal Ben D, Buccioni M, Lambertucci C, Thomas A, Volpini R - In Silico Pharmacol (2013)

Bottom Line: Results 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.The 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.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, Camerino, MC 62032 Italy.

ABSTRACT

Purpose: A2B 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.

Methods: The 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.

Results: Results 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.

Conclusions: The 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.

No MeSH data available.


Molecular structure of Ado and NECA.
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Fig1: Molecular structure of Ado and NECA.

Mentions: Adenosine (Ado, FigureĀ 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). Ado activity is mediated by the activation of four receptors that have been cloned (Robeva et al. 1996) and classified as A1, A2A, A2B, and A3 adenosine receptor (AR) subtypes (Fredholm et al. 2001) by considering the respective coupling to second messengers. Furthermore, 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.Figure 1


Simulation and comparative analysis of binding modes of nucleoside and non-nucleoside agonists at the A2B adenosine receptor.

Dal Ben D, Buccioni M, Lambertucci C, Thomas A, Volpini R - In Silico Pharmacol (2013)

Molecular structure of Ado and NECA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215817&req=5

Fig1: Molecular structure of Ado and NECA.
Mentions: Adenosine (Ado, FigureĀ 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). Ado activity is mediated by the activation of four receptors that have been cloned (Robeva et al. 1996) and classified as A1, A2A, A2B, and A3 adenosine receptor (AR) subtypes (Fredholm et al. 2001) by considering the respective coupling to second messengers. Furthermore, 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.Figure 1

Bottom Line: Results 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.The 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.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, Camerino, MC 62032 Italy.

ABSTRACT

Purpose: A2B 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.

Methods: The 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.

Results: Results 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.

Conclusions: The 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.

No MeSH data available.