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

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.

Simulation and Comparative Analysis of Different Binding Modes of Non‐nucleoside Agonists at the A2AAdenosine Receptor

“…The binding mode 4 (Figure D) presents the compounds oriented in a similar way to the one previously described in literature for analogue agonists at the A 2B AR ,,. In detail, the N1 atom and the 6‐amino group of pyridines (or the N3 atom and the 4‐amino group of pyrimidines) give polar interaction with the amine and/or carbonyl groups of Asn253 6.55 amide function, respectively.…”

Molecular dynamics simulation and NMR investigation of the association of the β-blockers atenolol and propranolol with a chiral molecular micelle

“…During the docking procedure, the MM was set as the receptor and was structurally rigid, while the propranolol or atenolol ligands were set as completely flexible. MOE used the London dG scoring function to score each of the docking poses [37]. Of the hundreds of docked structures examined in this analysis, the thirty top-scoring poses were saved by the MOE software and constructed for future study.…”

“…Of the hundreds of docked structures examined in this analysis, the thirty top-scoring poses were saved by the MOE software and constructed for future study. The best scoring structures for each of the separate binding sites were then used in the subsequent MD simulation studies [37]. It should be noted that there was a high degree of structural similarity among the top-scoring docking structures from the MOE analysis.…”

A molecular dynamics simulation study of the association of 1,1′-binaphthyl-2,2′-diyl hydrogenphosphate enantiomers with a chiral molecular micelle

“…During each binding procedure, the London dG scoring function implemented in MOE was employed to estimate the free energy of binding of the ligand from a given pose. A total of 30 top-score docking poses were constructed and the best scoring MM-BNP complexes in the specific site were selected for the further MD simulation study [41]. …”