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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.


Plot of interaction energies for residues belonging to the section 1 of the A2BAR binding site, calculated with the MOEIF-E 6.0tool. Data are represented as kcal mol-1. The blue and red versions of the plots represent the results obtained at the 2YDO- and 3QAK-A2BAR models, respectively. Plots A and B are referred to the interaction energies of nucleoside derivatives 1–6, while plots C and D are referred to the non-nucleoside derivatives 7–12.
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Fig6: Plot of interaction energies for residues belonging to the section 1 of the A2BAR binding site, calculated with the MOEIF-E 6.0tool. Data are represented as kcal mol-1. The blue and red versions of the plots represent the results obtained at the 2YDO- and 3QAK-A2BAR models, respectively. Plots A and B are referred to the interaction energies of nucleoside derivatives 1–6, while plots C and D are referred to the non-nucleoside derivatives 7–12.

Mentions: A second approach to compare the binding modes of the different families of compounds at A2BAR consists in evaluating the interaction of ligands with each binding site residue, obtaining a set of data representing the different effect of the A2BAR residues during the ligand-target interaction. This analysis has been performed by the use of the IF-E 6.0 (Shadnia et al. 2009) tool retrievable at the SVL exchange service. This method was already used by our research group for the analysis of ligand-target interaction for a series of potent A3AR agonists (Dal Ben et al. 2010a). The script calculates and displays atomic and residue interaction forces as 3D vectors. It also calculates the per-residue interaction energies (values in kcal mol-1), where negative and positive energy values are associated to favourable and unfavourable interactions, respectively. The script has been applied to each compound at both A2BAR models. To display the results, the binding site residues are divided in three sections (Figure 5). The section 1 contains residues belonging to TM1 (Tyr101.35 and Glu141.39), TM2 (Ala642.61, Ile672.64, and Ser682.65), and TM7 (Ile2767.39, Ser2797.42, and His2807.43) domains, with the insertion also of Val853.32, Phe173 (EL2), and Val2506.51. These residues represent the receptor region interacting with ligand adenine and pyridine scaffolds and with the substituents at the 2-position of nucleosides and at the 3- and 4-positions of pyridines. Residues interacting with part of ribose atoms of nucleoside derivatives are also included in this section. Figure 6 represents the obtained results for section 1. The blue and red versions of the plots represent the results obtained at the 2YDO- and 3QAK-A2BAR models, respectively. In agreement with what appears from the superimposition of docking conformations (see above), the effect of these residues is different from nucleoside to non-nucleoside ligands as in the first case the 2-substituent of nucleosides is present only in some cases and presents different structural and chemical profiles, while in the second case the 4-substituent of pyridines is large and forming various interactions with binding site residues. In detail, considering the nucleoside derivatives 1–6, it clearly appears the effect of Phe173, Ser2797.42, and His2807.43 in stabilizing the ligand-target interaction. In particular, Phe173 is the key residue for stabilizing the scaffold position within the binding site through a π-stacking interaction, while Ser2797.42 and His2807.43 are involved in polar interaction with 2′- and 3′-hydroxyl groups of nucleosides. The further contribution of Val2506.51 and Ile2767.39 for scaffold stabilization is more evident at 2YDO-A2BAR model, while the role of the carbonyl group of Ile672.64 backbone atoms in forming H-bond interaction with the hydroxyl group of 2-substituent of 1 and 6 is clearly evident at 3QAK-based model. The latter residue forms also hydrophobic interaction with the alkynyl group of the nucleosides 1 and 6 (3QAK-based model). Considering the non-nucleoside derivatives 7–12, results highlight the role of Val853.32, Phe173, and Val2506.51 in stabilizing the ligand scaffold, while the interaction with Ser2797.42 and His2807.43 is lacking (see above). Tyr101.35 interacts with compound 12 in 3QAK-based model. Ile672.64 forms hydrophobic interaction with the 4-aromatic group of pyridines, while Ala642.61 forms on the one hand a stable H-bond interaction with the para-hydroxyl group of the 4-aromatic substituent of compound 8 (3QAK-based model), on the other hand a hydrophobic interaction with 4-aromatic group of 12. Comparing the results for this section with previously reported data, it can be underlined that Tyr101.35 showed to be critical for compound 12 activity as evidenced from mutagenesis results (Thimm et al. 2013), while Ile672.64 and Ala642.61 were already reported to possibly interact with the 4-substituent of pyridine derivatives (Sherbiny et al. 2009). The effect of Ser2797.42 and His2807.43 is evident for nucleoside agonists but not so well defined for non-nucleoside derivatives. In particular, the mutation of Ser2797.42 to alanine takes to a loss of activity of nucleosides and, on the contrary, to an improvement of non-nucleoside derivative EC50 data (Thimm et al. 2013). These results are confirmed at the A2AAR (Lane et al. 2012). Our study confirms the effect on nucleosides but does not highlight a direct interaction with non-nucleoside derivatives. The histidine residue in position 7.43 of ARs (His2807.43 in A2BAR) 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 A2BAR with ligands, it has been recently reported a molecular modelling study consisting in the rebuilding of the three AR models other than A2AAR 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 A2BAR, this study suggests a possible direct contact of His2807.43 with a potent thiazole antagonist. Further recent studies report that the mutation of this histidine leads to a loss of interaction with ligands (Thimm et al. 2013). As reported above, our modelling study does not highlight a direct contact of His2807.43 with non-nucleoside derivatives even if we cannot exclude that an interaction of these ligands with this residue and Ser2797.42 could be mediated by a water molecule.Figure 5


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)

Plot of interaction energies for residues belonging to the section 1 of the A2BAR binding site, calculated with the MOEIF-E 6.0tool. Data are represented as kcal mol-1. The blue and red versions of the plots represent the results obtained at the 2YDO- and 3QAK-A2BAR models, respectively. Plots A and B are referred to the interaction energies of nucleoside derivatives 1–6, while plots C and D are referred to the non-nucleoside derivatives 7–12.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig6: Plot of interaction energies for residues belonging to the section 1 of the A2BAR binding site, calculated with the MOEIF-E 6.0tool. Data are represented as kcal mol-1. The blue and red versions of the plots represent the results obtained at the 2YDO- and 3QAK-A2BAR models, respectively. Plots A and B are referred to the interaction energies of nucleoside derivatives 1–6, while plots C and D are referred to the non-nucleoside derivatives 7–12.
Mentions: A second approach to compare the binding modes of the different families of compounds at A2BAR consists in evaluating the interaction of ligands with each binding site residue, obtaining a set of data representing the different effect of the A2BAR residues during the ligand-target interaction. This analysis has been performed by the use of the IF-E 6.0 (Shadnia et al. 2009) tool retrievable at the SVL exchange service. This method was already used by our research group for the analysis of ligand-target interaction for a series of potent A3AR agonists (Dal Ben et al. 2010a). The script calculates and displays atomic and residue interaction forces as 3D vectors. It also calculates the per-residue interaction energies (values in kcal mol-1), where negative and positive energy values are associated to favourable and unfavourable interactions, respectively. The script has been applied to each compound at both A2BAR models. To display the results, the binding site residues are divided in three sections (Figure 5). The section 1 contains residues belonging to TM1 (Tyr101.35 and Glu141.39), TM2 (Ala642.61, Ile672.64, and Ser682.65), and TM7 (Ile2767.39, Ser2797.42, and His2807.43) domains, with the insertion also of Val853.32, Phe173 (EL2), and Val2506.51. These residues represent the receptor region interacting with ligand adenine and pyridine scaffolds and with the substituents at the 2-position of nucleosides and at the 3- and 4-positions of pyridines. Residues interacting with part of ribose atoms of nucleoside derivatives are also included in this section. Figure 6 represents the obtained results for section 1. The blue and red versions of the plots represent the results obtained at the 2YDO- and 3QAK-A2BAR models, respectively. In agreement with what appears from the superimposition of docking conformations (see above), the effect of these residues is different from nucleoside to non-nucleoside ligands as in the first case the 2-substituent of nucleosides is present only in some cases and presents different structural and chemical profiles, while in the second case the 4-substituent of pyridines is large and forming various interactions with binding site residues. In detail, considering the nucleoside derivatives 1–6, it clearly appears the effect of Phe173, Ser2797.42, and His2807.43 in stabilizing the ligand-target interaction. In particular, Phe173 is the key residue for stabilizing the scaffold position within the binding site through a π-stacking interaction, while Ser2797.42 and His2807.43 are involved in polar interaction with 2′- and 3′-hydroxyl groups of nucleosides. The further contribution of Val2506.51 and Ile2767.39 for scaffold stabilization is more evident at 2YDO-A2BAR model, while the role of the carbonyl group of Ile672.64 backbone atoms in forming H-bond interaction with the hydroxyl group of 2-substituent of 1 and 6 is clearly evident at 3QAK-based model. The latter residue forms also hydrophobic interaction with the alkynyl group of the nucleosides 1 and 6 (3QAK-based model). Considering the non-nucleoside derivatives 7–12, results highlight the role of Val853.32, Phe173, and Val2506.51 in stabilizing the ligand scaffold, while the interaction with Ser2797.42 and His2807.43 is lacking (see above). Tyr101.35 interacts with compound 12 in 3QAK-based model. Ile672.64 forms hydrophobic interaction with the 4-aromatic group of pyridines, while Ala642.61 forms on the one hand a stable H-bond interaction with the para-hydroxyl group of the 4-aromatic substituent of compound 8 (3QAK-based model), on the other hand a hydrophobic interaction with 4-aromatic group of 12. Comparing the results for this section with previously reported data, it can be underlined that Tyr101.35 showed to be critical for compound 12 activity as evidenced from mutagenesis results (Thimm et al. 2013), while Ile672.64 and Ala642.61 were already reported to possibly interact with the 4-substituent of pyridine derivatives (Sherbiny et al. 2009). The effect of Ser2797.42 and His2807.43 is evident for nucleoside agonists but not so well defined for non-nucleoside derivatives. In particular, the mutation of Ser2797.42 to alanine takes to a loss of activity of nucleosides and, on the contrary, to an improvement of non-nucleoside derivative EC50 data (Thimm et al. 2013). These results are confirmed at the A2AAR (Lane et al. 2012). Our study confirms the effect on nucleosides but does not highlight a direct interaction with non-nucleoside derivatives. The histidine residue in position 7.43 of ARs (His2807.43 in A2BAR) 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 A2BAR with ligands, it has been recently reported a molecular modelling study consisting in the rebuilding of the three AR models other than A2AAR 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 A2BAR, this study suggests a possible direct contact of His2807.43 with a potent thiazole antagonist. Further recent studies report that the mutation of this histidine leads to a loss of interaction with ligands (Thimm et al. 2013). As reported above, our modelling study does not highlight a direct contact of His2807.43 with non-nucleoside derivatives even if we cannot exclude that an interaction of these ligands with this residue and Ser2797.42 could be mediated by a water molecule.Figure 5

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.