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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.


Sequence alignment of the four human AR subtypes. Transmembrane (TM), intracellular loop (IL), extracellular loop (EL), and C-terminal (C-TERM) domains are indicated; * symbols indicate sequence identity in all the four subtypes; C letters indicate cysteine residues involved in the disulfide bridge conserved among the four AR subtypes; letters coloured in yellow, cyan, and green indicate the A2BAR binding site residues involved in ligand interaction (the colour indexing refers to the binding site subdivision described in Figure 5, see its legend for details).
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Fig2: Sequence alignment of the four human AR subtypes. Transmembrane (TM), intracellular loop (IL), extracellular loop (EL), and C-terminal (C-TERM) domains are indicated; * symbols indicate sequence identity in all the four subtypes; C letters indicate cysteine residues involved in the disulfide bridge conserved among the four AR subtypes; letters coloured in yellow, cyan, and green indicate the A2BAR binding site residues involved in ligand interaction (the colour indexing refers to the binding site subdivision described in Figure 5, see its legend for details).

Mentions: To simulate the binding mode of nucleoside and non-nucleoside 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). The availability of crystal structure the A2AAR allows to improve the accuracy of AR homology models, due to the high residue conservation in the primary sequences of the AR subtypes (see Figure 2), sharing a sequence identity of ~57% within the TM domains (Dal Ben et al. 2010b). The residues located within the seven TM domains in the upper part of ARs, corresponding to the ligand binding site, present a conservation (identity) at about 71% (Costanzi et al. 2007). The obtained A2BAR 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 A2BAR models contain a disulfide bridge given by two cysteine residues belonging to TM3 and extracellular loop (EL) 2 domains (Cys783.25 - 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


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)

Sequence alignment of the four human AR subtypes. Transmembrane (TM), intracellular loop (IL), extracellular loop (EL), and C-terminal (C-TERM) domains are indicated; * symbols indicate sequence identity in all the four subtypes; C letters indicate cysteine residues involved in the disulfide bridge conserved among the four AR subtypes; letters coloured in yellow, cyan, and green indicate the A2BAR binding site residues involved in ligand interaction (the colour indexing refers to the binding site subdivision described in Figure 5, see its legend for details).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Sequence alignment of the four human AR subtypes. Transmembrane (TM), intracellular loop (IL), extracellular loop (EL), and C-terminal (C-TERM) domains are indicated; * symbols indicate sequence identity in all the four subtypes; C letters indicate cysteine residues involved in the disulfide bridge conserved among the four AR subtypes; letters coloured in yellow, cyan, and green indicate the A2BAR binding site residues involved in ligand interaction (the colour indexing refers to the binding site subdivision described in Figure 5, see its legend for details).
Mentions: To simulate the binding mode of nucleoside and non-nucleoside 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). The availability of crystal structure the A2AAR allows to improve the accuracy of AR homology models, due to the high residue conservation in the primary sequences of the AR subtypes (see Figure 2), sharing a sequence identity of ~57% within the TM domains (Dal Ben et al. 2010b). The residues located within the seven TM domains in the upper part of ARs, corresponding to the ligand binding site, present a conservation (identity) at about 71% (Costanzi et al. 2007). The obtained A2BAR 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 A2BAR models contain a disulfide bridge given by two cysteine residues belonging to TM3 and extracellular loop (EL) 2 domains (Cys783.25 - 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

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.