Limits...
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 3 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
getmorefigures.php?uid=PMC4215817&req=5

Fig8: Plot of interaction energies for residues belonging to the section 3 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: The section 3 contains residues located close or at the entrance of the binding site and belonging to EL2 (Leu172, Glu174, and Met179), TM6 (Val2536.54, Asn2546.55, and Thr2576.58), EL3 (Asn266, Lys267, Pro268, and Lys269), and TM7 (Met2727.35). These residues are involved in interaction with the purine and the pyridine scaffold, the C2– and N6-substituents of nucleosides, and the 4-aromatic substituent, the 5-cyano group, and the 6-amino function of pyridines. Even in this case, the representation is divided in plots for nucleoside and non-nucleoside derivatives at the two 2YDO- and 3QAK-A2BAR models (Figure 8). The results confirm the key role of Asn2546.55 for the interaction with both families of ligands at both receptor models. The importance of this residue for the interaction of A2BAR 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. The carboxyl function of this residue can interact with the unsubstituted 6-amino group (1, 2, 6) or with polar hydrogens present within the N6-substituent (3–5). In the case of pyridine derivatives, the effect of this residue is influenced by its conformation, as in the 2YDO-based A2BAR model its carboxyl group points towards the 6-amino function of ligands providing H-bond interaction, while in the case of 3QAK-based model the side chain is oriented towards the extracellular environment in proximity of Lys269. Analogue consideration can be made for Lys269, whose side chain points towards Glu174 and the N6-substituent of nucleoside derivatives. In the case of compounds 1 and 6, the charged amino group of this lysine interacts also with the hydroxyl group within the 2-substituent. In the case of the non-nucleoside derivatives, the Lys269 charged amino group is located in proximity of 5-cyano function without forming interaction with this group. The effect of the remaining amino acids in this section seems not significant.Figure 8


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 3 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

Fig8: Plot of interaction energies for residues belonging to the section 3 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: The section 3 contains residues located close or at the entrance of the binding site and belonging to EL2 (Leu172, Glu174, and Met179), TM6 (Val2536.54, Asn2546.55, and Thr2576.58), EL3 (Asn266, Lys267, Pro268, and Lys269), and TM7 (Met2727.35). These residues are involved in interaction with the purine and the pyridine scaffold, the C2– and N6-substituents of nucleosides, and the 4-aromatic substituent, the 5-cyano group, and the 6-amino function of pyridines. Even in this case, the representation is divided in plots for nucleoside and non-nucleoside derivatives at the two 2YDO- and 3QAK-A2BAR models (Figure 8). The results confirm the key role of Asn2546.55 for the interaction with both families of ligands at both receptor models. The importance of this residue for the interaction of A2BAR 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. The carboxyl function of this residue can interact with the unsubstituted 6-amino group (1, 2, 6) or with polar hydrogens present within the N6-substituent (3–5). In the case of pyridine derivatives, the effect of this residue is influenced by its conformation, as in the 2YDO-based A2BAR model its carboxyl group points towards the 6-amino function of ligands providing H-bond interaction, while in the case of 3QAK-based model the side chain is oriented towards the extracellular environment in proximity of Lys269. Analogue consideration can be made for Lys269, whose side chain points towards Glu174 and the N6-substituent of nucleoside derivatives. In the case of compounds 1 and 6, the charged amino group of this lysine interacts also with the hydroxyl group within the 2-substituent. In the case of the non-nucleoside derivatives, the Lys269 charged amino group is located in proximity of 5-cyano function without forming interaction with this group. The effect of the remaining amino acids in this section seems not significant.Figure 8

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.