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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.


Comparison of docking conformations. Superimposition of docking conformations of nucleoside (compound 5) and non-nucleoside (compound 12) derivatives at A2BAR at the 2YDO- and 3QAK-based A2BAR models (A and B, respectively). TM4 domain is partially hidden. The matching between functional groups presenting analogue properties among the two molecules are represented as pharmacophoric features (see text for details).
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Fig4: Comparison of docking conformations. Superimposition of docking conformations of nucleoside (compound 5) and non-nucleoside (compound 12) derivatives at A2BAR at the 2YDO- and 3QAK-based A2BAR models (A and B, respectively). TM4 domain is partially hidden. The matching between functional groups presenting analogue properties among the two molecules are represented as pharmacophoric features (see text for details).

Mentions: To evaluate the possible common features for the interaction with receptor binding site, the docking conformations of nucleoside and non-nucleoside agonists have been subjected to a comparative analysis performed and here presented considering two different points of views. Firstly, a direct comparison can be made by the superimposition of the representative docking conformations of one nucleoside and one non-nucleoside agonist, with the aim of obtaining, if present, a sort of pharmacophore description. In this sense, Figure 4 shows the superimposition of the docking conformations of compounds 5 and 12 (the most potent compounds from the two ligand families) at the two A2BAR models. The results of the superimposition are almost identical at the two receptor models and highlight the presence of a series of common interaction points that can be converted to pharmacophoric features. In details, the 6-amino group of nucleosides and pyridines are located in a similar position, providing a H-bond donor feature able to interact with the H-bond acceptor features given by the carbonyl group of Asn2546.55 and, in some cases, by the carboxyl group of Glu174 (EL2). Similarly, the N7 and N1 atoms of nucleosides and pyridines, respectively, are almost superimposed and represent a H-bond acceptor feature located in close proximity with the donor function given by the amine group belonging to amide function of Asn2546.55. Furthermore, the 4′-N-ethylcarboxamide function of the nucleoside derivative 5 presents the amide carbonyl group and polar hydrogen in a nearly identical position to the analogue functions of 2-thioacetamide group of compound 12, suggesting the importance of the presence in the ligand of a combination of H-bond acceptor and donor features located in that sub-region of the binding site. The carbonyl groups are located in close proximity to a polar hydrogen of His2516.52, while the polar hydrogens of the ligand amide groups are located near the polar oxygen of Thr893.36. While the pyridine derivatives present an amide function (compound 12) or an imidazole ring (7–11) both able to provide the two pharmacophoric features, in the case of nucleoside derivatives the two functions can be present only in the case of NECA derivatives (3–6), while the Ado analogues (1, 2) may fit only one of the two polar features. This data is observable already from the 2YDO and 3QAK crystal structures and could in any case explain the general behaviour at ARs according to which the Ado derivatives are generally less potent respect to the corresponding NECA or MECA (4′-N-methylcarboxamidoAdo) analogues. The docking position of the 3-cyano group of pyridines roughly corresponds to the position of the nucleosides 2′-hydroxyl function. As reported above, the cyano group is inserted in a sub-cavity between Val853.32, Leu863.33, Thr893.36, Ser2797.42, and His2807.43, with the presence of some space between this function and the polar groups of Ser2797.42 and His2807.43. In this sense, the possible presence of a water molecule providing a “bridge-interaction” between ligand and binding site residues could suggest the introduction of a sort of “polar group feature” corresponding to the presence of the 2′-hydroxyl function of nucleosides and the cyano group of pyridines. This polar group could interact with Ser2797.42 and His2807.43 residues directly (like in the case of nucleosides) or with the aid of a bridging water molecule (in the case of pyridines). The presence of a hydrophobic group at the 2-position of nucleosides and at the 4-position of pyridines suggests the presence of a large hydrophobic feature located within TM1, TM2, and TM7 domains. This group seems critical in particular for pyridine derivatives, as only some nucleoside agonists present a 2-hydrophobic substituent. Finally, the position of the N1 atom of nucleosides is almost coincident to the one of the nitrogen atom of the 5-cyano group of pyridines, suggesting a possible H-bond acceptor function in that position. However, it must be noted that these atoms are oriented towards the extracellular environment and the H-bond donor counterpart could be provided only by a special arrangement of Lys269 (EL3) side chain. We underline that the use of a pharmacophore model in this context is aimed only at helping for the description of an interaction pattern that appears conserved between nucleoside and non-nucleoside agonists. For a development of a proper pharmacophore model, a larger set of molecules and Ki affinity data should be employed.Figure 4


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)

Comparison of docking conformations. Superimposition of docking conformations of nucleoside (compound 5) and non-nucleoside (compound 12) derivatives at A2BAR at the 2YDO- and 3QAK-based A2BAR models (A and B, respectively). TM4 domain is partially hidden. The matching between functional groups presenting analogue properties among the two molecules are represented as pharmacophoric features (see text for details).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Comparison of docking conformations. Superimposition of docking conformations of nucleoside (compound 5) and non-nucleoside (compound 12) derivatives at A2BAR at the 2YDO- and 3QAK-based A2BAR models (A and B, respectively). TM4 domain is partially hidden. The matching between functional groups presenting analogue properties among the two molecules are represented as pharmacophoric features (see text for details).
Mentions: To evaluate the possible common features for the interaction with receptor binding site, the docking conformations of nucleoside and non-nucleoside agonists have been subjected to a comparative analysis performed and here presented considering two different points of views. Firstly, a direct comparison can be made by the superimposition of the representative docking conformations of one nucleoside and one non-nucleoside agonist, with the aim of obtaining, if present, a sort of pharmacophore description. In this sense, Figure 4 shows the superimposition of the docking conformations of compounds 5 and 12 (the most potent compounds from the two ligand families) at the two A2BAR models. The results of the superimposition are almost identical at the two receptor models and highlight the presence of a series of common interaction points that can be converted to pharmacophoric features. In details, the 6-amino group of nucleosides and pyridines are located in a similar position, providing a H-bond donor feature able to interact with the H-bond acceptor features given by the carbonyl group of Asn2546.55 and, in some cases, by the carboxyl group of Glu174 (EL2). Similarly, the N7 and N1 atoms of nucleosides and pyridines, respectively, are almost superimposed and represent a H-bond acceptor feature located in close proximity with the donor function given by the amine group belonging to amide function of Asn2546.55. Furthermore, the 4′-N-ethylcarboxamide function of the nucleoside derivative 5 presents the amide carbonyl group and polar hydrogen in a nearly identical position to the analogue functions of 2-thioacetamide group of compound 12, suggesting the importance of the presence in the ligand of a combination of H-bond acceptor and donor features located in that sub-region of the binding site. The carbonyl groups are located in close proximity to a polar hydrogen of His2516.52, while the polar hydrogens of the ligand amide groups are located near the polar oxygen of Thr893.36. While the pyridine derivatives present an amide function (compound 12) or an imidazole ring (7–11) both able to provide the two pharmacophoric features, in the case of nucleoside derivatives the two functions can be present only in the case of NECA derivatives (3–6), while the Ado analogues (1, 2) may fit only one of the two polar features. This data is observable already from the 2YDO and 3QAK crystal structures and could in any case explain the general behaviour at ARs according to which the Ado derivatives are generally less potent respect to the corresponding NECA or MECA (4′-N-methylcarboxamidoAdo) analogues. The docking position of the 3-cyano group of pyridines roughly corresponds to the position of the nucleosides 2′-hydroxyl function. As reported above, the cyano group is inserted in a sub-cavity between Val853.32, Leu863.33, Thr893.36, Ser2797.42, and His2807.43, with the presence of some space between this function and the polar groups of Ser2797.42 and His2807.43. In this sense, the possible presence of a water molecule providing a “bridge-interaction” between ligand and binding site residues could suggest the introduction of a sort of “polar group feature” corresponding to the presence of the 2′-hydroxyl function of nucleosides and the cyano group of pyridines. This polar group could interact with Ser2797.42 and His2807.43 residues directly (like in the case of nucleosides) or with the aid of a bridging water molecule (in the case of pyridines). The presence of a hydrophobic group at the 2-position of nucleosides and at the 4-position of pyridines suggests the presence of a large hydrophobic feature located within TM1, TM2, and TM7 domains. This group seems critical in particular for pyridine derivatives, as only some nucleoside agonists present a 2-hydrophobic substituent. Finally, the position of the N1 atom of nucleosides is almost coincident to the one of the nitrogen atom of the 5-cyano group of pyridines, suggesting a possible H-bond acceptor function in that position. However, it must be noted that these atoms are oriented towards the extracellular environment and the H-bond donor counterpart could be provided only by a special arrangement of Lys269 (EL3) side chain. We underline that the use of a pharmacophore model in this context is aimed only at helping for the description of an interaction pattern that appears conserved between nucleoside and non-nucleoside agonists. For a development of a proper pharmacophore model, a larger set of molecules and Ki affinity data should be employed.Figure 4

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.