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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.


Results of docking studies. Docking conformations of nucleoside (compound 5: A-B; TM4 domain is partially hidden) and non-nucleoside (compound 12: C-D) derivatives at the 2YDO-based A2BAR model and ligand-target interaction plots as computed by MOE software.
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Fig3: Results of docking studies. Docking conformations of nucleoside (compound 5: A-B; TM4 domain is partially hidden) and non-nucleoside (compound 12: C-D) derivatives at the 2YDO-based A2BAR model and ligand-target interaction plots as computed by MOE software.

Mentions: Considering the nucleoside agonists, the docking conformations share a common motif, presenting the Ado/NECA derivatives located in the binding site similarly to the co-crystallized nucleoside agonists. In detail, adenine scaffold is positioned between TM3, TM6, and TM7, with the 8- and 9-positions pointing towards the core of the receptor, while the 2- and N6-substituents are externally located (Figure 3A-B). The adenine plane is stabilized by an aromatic stacking interaction with the AR conserved phenylalanine residue in EL2 domain (Phe173 in A2BAR), while the N6-amino group and the N7 atom interact through H-bonding with a conserved asparagine (Asn2546.55 in A2BAR). The N6-amino group makes also H-bonding with Glu174 in the case of the 2YDO-based A2BAR model but not in the case of the 3QAK-based model, due to the different orientation of the amino acid side chain. Considering again the 2YDO-based A2BAR model, in the case of the presence of substituents at the N6-position of ligands (compounds 3–5), a rearrangement of Glu174 side chain is observed during post-docking minimization stage. The obtained conformation of the amino acid is comparable to the one of the corresponding residue in the 3QAK-based model and is able to make a polar interaction with Lys269. The N6-substituents contain polar groups able to give polar interactions with residues in their proximity. In particular, compounds 3 and 4 contain a substituted carbonyl-hydrazine at the 6-position, with the two polar hydrogens of hydrazine group oppositely oriented and pointing towards Asn2546.55 and Glu174 polar oxygens. In the case of compound 5, the phenyl ring directly bound to the N6-amine group causes a major rearrangement of Glu174 side chain (2YDO-based A2BAR model) during post-docking minimization step, leading to a conformation highly similar to the same residue in 3QAK-based model. The obtained minimized systems present in both cases the Glu174- Lys269 polar interaction, with an additional H-bonding between Glu174 and the polar hydrogen atom of amide function within the N6-substituent. Further polar interaction is possible between the carbonyl group of the same amide function of 5 and the side chain of Asn266 (EL3). The 2-substituent (compounds 1, 2, 4–6) is located between TM1, TM2, TM7, and EL2 with the position of phenyl ring (compounds 1, 2, 6) roughly corresponding to the one occupied by the urea group within the 2-substituent of co-crystallized UK-432097 agonist. The ribose moiety is located into the TM helices bundle, in a region between TM2, TM3, TM6, and TM7 in close proximity to the conserved tryptophan (Trp2476.48 in A2BAR) side chain. The ribose ring presents the hydroxyl groups at the 2′- and 3′-position giving H-bond interaction with A2BAR His2807.43 and Ser2797.42 side chains, respectively. The Ado derivatives (1–2) present in 4′-position a hydroxymethyl group located between TM3 and TM6 and interacting with His2516.52 side chain, while the 4′-ethylcarboxamido substituent of NECA derivatives (3–6) is located in analogue position and gives H-bond interaction with Thr893.36 and His2516.52.Figure 3


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)

Results of docking studies. Docking conformations of nucleoside (compound 5: A-B; TM4 domain is partially hidden) and non-nucleoside (compound 12: C-D) derivatives at the 2YDO-based A2BAR model and ligand-target interaction plots as computed by MOE software.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Results of docking studies. Docking conformations of nucleoside (compound 5: A-B; TM4 domain is partially hidden) and non-nucleoside (compound 12: C-D) derivatives at the 2YDO-based A2BAR model and ligand-target interaction plots as computed by MOE software.
Mentions: Considering the nucleoside agonists, the docking conformations share a common motif, presenting the Ado/NECA derivatives located in the binding site similarly to the co-crystallized nucleoside agonists. In detail, adenine scaffold is positioned between TM3, TM6, and TM7, with the 8- and 9-positions pointing towards the core of the receptor, while the 2- and N6-substituents are externally located (Figure 3A-B). The adenine plane is stabilized by an aromatic stacking interaction with the AR conserved phenylalanine residue in EL2 domain (Phe173 in A2BAR), while the N6-amino group and the N7 atom interact through H-bonding with a conserved asparagine (Asn2546.55 in A2BAR). The N6-amino group makes also H-bonding with Glu174 in the case of the 2YDO-based A2BAR model but not in the case of the 3QAK-based model, due to the different orientation of the amino acid side chain. Considering again the 2YDO-based A2BAR model, in the case of the presence of substituents at the N6-position of ligands (compounds 3–5), a rearrangement of Glu174 side chain is observed during post-docking minimization stage. The obtained conformation of the amino acid is comparable to the one of the corresponding residue in the 3QAK-based model and is able to make a polar interaction with Lys269. The N6-substituents contain polar groups able to give polar interactions with residues in their proximity. In particular, compounds 3 and 4 contain a substituted carbonyl-hydrazine at the 6-position, with the two polar hydrogens of hydrazine group oppositely oriented and pointing towards Asn2546.55 and Glu174 polar oxygens. In the case of compound 5, the phenyl ring directly bound to the N6-amine group causes a major rearrangement of Glu174 side chain (2YDO-based A2BAR model) during post-docking minimization step, leading to a conformation highly similar to the same residue in 3QAK-based model. The obtained minimized systems present in both cases the Glu174- Lys269 polar interaction, with an additional H-bonding between Glu174 and the polar hydrogen atom of amide function within the N6-substituent. Further polar interaction is possible between the carbonyl group of the same amide function of 5 and the side chain of Asn266 (EL3). The 2-substituent (compounds 1, 2, 4–6) is located between TM1, TM2, TM7, and EL2 with the position of phenyl ring (compounds 1, 2, 6) roughly corresponding to the one occupied by the urea group within the 2-substituent of co-crystallized UK-432097 agonist. The ribose moiety is located into the TM helices bundle, in a region between TM2, TM3, TM6, and TM7 in close proximity to the conserved tryptophan (Trp2476.48 in A2BAR) side chain. The ribose ring presents the hydroxyl groups at the 2′- and 3′-position giving H-bond interaction with A2BAR His2807.43 and Ser2797.42 side chains, respectively. The Ado derivatives (1–2) present in 4′-position a hydroxymethyl group located between TM3 and TM6 and interacting with His2516.52 side chain, while the 4′-ethylcarboxamido substituent of NECA derivatives (3–6) is located in analogue position and gives H-bond interaction with Thr893.36 and His2516.52.Figure 3

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.