“…The obtained A 2B AR homology models were checked by using the Protein Geometry Monitor application within MOE (Environment), which provides a variety of stereochemical measurements for inspection of the structural quality in a given protein, such as backbone bond lengths, angles and dihedrals, Ramachandran φ-ψ dihedral plots, and quality of side chain rotamer and non-bonded contact. The final A 2B AR models contain a disulfide bridge given by two cysteine residues belonging to TM3 and extracellular loop (EL) 2 domains (Cys78 3.25 - where 3.25 indicates the residue position within helix (Ballesteros and Weinstein 1995) - and Cys171, respectively), in agreement with recent mutagenesis studies (Schiedel et al 2011) and as observed in the case of recently reported modelling analyses on this AR subtype (Sherbiny et al 2009; Thimm et al 2013; Inamdar et al 2013). Figure 2
Sequence alignment of the four human AR subtypes.…”
Section: Resultssupporting
confidence: 86%
“…The results confirm the key role of Asn254 6.55 for the interaction with both families of ligands at both receptor models. The importance of this residue for the interaction of A 2B AR with ligands has been highlighted even in recently reported studies (Sherbiny et al 2009; Inamdar et al 2013). Furthermore, it appears a relevant effect of Glu174 for the interaction with nucleoside derivatives 1–6.…”
Section: Resultsmentioning
confidence: 99%
“…The histidine residue in position 7.43 of ARs (His280 7.43 in A 2B AR) is reported to be essential for receptor expression and function (Dal Ben et al 2010b; Thimm et al 2013). Considering the interaction of this residue in A 2B AR with ligands, it has been recently reported a molecular modelling study consisting in the rebuilding of the three AR models other than A 2A AR and the use of the four AR 3D structures for a molecular docking study of antagonists followed by molecular dynamics analysis (Inamdar et al 2013). Considering the results at the A 2B AR, this study suggests a possible direct contact of His280 7.43 with a potent thiazole antagonist.…”
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.
“…The obtained A 2B AR homology models were checked by using the Protein Geometry Monitor application within MOE (Environment), which provides a variety of stereochemical measurements for inspection of the structural quality in a given protein, such as backbone bond lengths, angles and dihedrals, Ramachandran φ-ψ dihedral plots, and quality of side chain rotamer and non-bonded contact. The final A 2B AR models contain a disulfide bridge given by two cysteine residues belonging to TM3 and extracellular loop (EL) 2 domains (Cys78 3.25 - where 3.25 indicates the residue position within helix (Ballesteros and Weinstein 1995) - and Cys171, respectively), in agreement with recent mutagenesis studies (Schiedel et al 2011) and as observed in the case of recently reported modelling analyses on this AR subtype (Sherbiny et al 2009; Thimm et al 2013; Inamdar et al 2013). Figure 2
Sequence alignment of the four human AR subtypes.…”
Section: Resultssupporting
confidence: 86%
“…The results confirm the key role of Asn254 6.55 for the interaction with both families of ligands at both receptor models. The importance of this residue for the interaction of A 2B AR with ligands has been highlighted even in recently reported studies (Sherbiny et al 2009; Inamdar et al 2013). Furthermore, it appears a relevant effect of Glu174 for the interaction with nucleoside derivatives 1–6.…”
Section: Resultsmentioning
confidence: 99%
“…The histidine residue in position 7.43 of ARs (His280 7.43 in A 2B AR) is reported to be essential for receptor expression and function (Dal Ben et al 2010b; Thimm et al 2013). Considering the interaction of this residue in A 2B AR with ligands, it has been recently reported a molecular modelling study consisting in the rebuilding of the three AR models other than A 2A AR and the use of the four AR 3D structures for a molecular docking study of antagonists followed by molecular dynamics analysis (Inamdar et al 2013). Considering the results at the A 2B AR, this study suggests a possible direct contact of His280 7.43 with a potent thiazole antagonist.…”
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.
“…This hypothetical binding mode agrees reasonably well with the co-crystallized ligands in the 3EML and 3UZC protein structures (Figure 2 a). [28,34] Previous results also showed the importance of residue Asn 6.55 in ligand recognition. [10,35] Compound 10, with good affinity for hA 1 , hA 2A , and hA 3 ARs, displayed the described binding mode in all the three ARs (Figure 2 b-d).…”
A study focused on the discovery of new chemical entities based on the 3-arylcoumarin scaffold was performed with the aim of finding new adenosine receptor (AR) ligands. Thirteen synthesized compounds were evaluated by radioligand binding (A1, A2A, and A3) and adenylyl cyclase activity (A2B) assays in order to study their affinity for the four human AR (hAR) subtypes. Seven of the studied compounds proved to be selective A3 AR ligands, with 3-(4'-methylphenyl)-8-(2-oxopropoxy)coumarin (12) being the most potent (Ki =634 nM). None of the compounds showed affinity for the A2B receptor, while four compounds were found to be nonselective AR ligands for the other three subtypes. Docking simulations were carried out to identify the hypothetical binding mode and to rationalize the interaction of these types of coumarin derivatives with the binding site of the three ARs to which binding was observed. The results allowed us to conclude that the 3-arylcoumarin scaffold composes a novel and promising class of A3 AR ligands. ADME properties were also calculated, with the results suggesting that these compounds are promising leads for the identification of new drug candidates.
“…Ligand similarity biased template selection criteria at the basis of the “Best Template Searching” tool has been successfully applied to rationalize the Structure Activity Relationships (SAR) of a series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] furamides as antagonist of the hARs (Inamdar et al 2013 ). The most potent derivative of the furamides series, the furan-2-carboxylic acid (4-phenyl-5-pyridin-4-yl-thiazol-2-yl)-amide, has been selected as query molecule: As reported in Table 2 , a similarity sorting of the templates based on the combined similarity criteria has been taken into account to select the most suitable models for receptor-based ligand design.…”
BackgroundAdenosine receptors (ARs) belong to the G protein-coupled receptors (GCPRs) family. The recent release of X-ray structures of the human A2A AR (h A2A AR ) in complex with agonists and antagonists has increased the application of structure-based drug design approaches to this class of receptors. Among them, homology modeling represents the method of choice to gather structural information on the other receptor subtypes, namely A1, A2B, and A3 ARs. With the aim of helping users in the selection of either a template to build its own models or ARs homology models publicly available on our platform, we implemented our web-resource dedicated to ARs, Adenosiland, with the “Best Template Searching” facility. This tool is freely accessible at the following web address: http://mms.dsfarm.unipd.it/Adenosiland/ligand.php.FindingsThe template suggestions and homology models provided by the “Best Template Searching” tool are guided by the similarity of a query structure (putative or known ARs ligand) with all ligands co-crystallized with hA2A AR subtype. The tool computes several similarity indexes and sort the outcoming results according to the index selected by the user.ConclusionsWe have implemented our web-resource dedicated to ARs Adenosiland with the “Best Template Searching” facility, a tool to guide template and models selection for hARs modelling. The underlying idea of our new facility, that is the selection of a template (or models built upon a template) whose co-crystallized ligand shares the highest similarity with the query structure, can be easily extended to other GPCRs.
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