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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 2 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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Fig7: Plot of interaction energies for residues belonging to the section 2 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 2 contains residues belonging to TM3 (Leu863.33, Thr893.36, Gln903.37, and Ile933.40), TM5 (Met1825.38, Asn1865.42, Cys1905.46, and Val1915.47), and TM6 (Trp2476.48 and His2516.52). These residues are involved in interaction with ribose group of nucleoside analogues (in particular the 4′-position) and with 2-substituent of non-nucleoside pyridine derivatives. Figure 7 represents the obtained results for section 2, again with blue and red versions corresponding to the 2YDO- and 3QAK-A2BAR models, respectively. The effect of the receptor residues for the interaction with ligands is comparable considering both nucleoside and non-nucleoside agonists. Firstly, Leu863.33 and Met1825.38 form a hydrophobic interaction with the ribose group of nucleosides and with the 2-substituent of pyridines. Secondly, it appears evident the contribution of Thr893.36 and His2516.52, in accordance with the results of superimposition experiments (see above). In particular, Thr893.36 provide a stabilizing effect for the polar hydrogen of NECAs 5′-amide group from 3–6, of thiomethylimidazole from 7–11, and of thioacetamide from 12. The effect of this residue is largely reduced in the case of the two Ado derivatives 1–2 that do not present a combination of H-bond acceptor and donor features at the 5′-position. His2516.52 cooperates with Thr893.36 in providing a stabilizing effect for ligands. In the case of non-nucleoside derivatives, it is interesting to notate the greater effect of this residue for 12 respect to 7–11 at both A2BAR models, suggesting a better interaction of His2516.52 for the amide function respect to an imidazole ring. The effect of the other residues of this section is not significant, with the exception in some cases of Gln903.37 (polar interaction with non-nucleoside derivatives in 3QAK-A2BAR model) and Trp2476.48. In a previous study (Sherbiny et al. 2009), Thr893.36 was suggested as interacting with 3-cyano substituent of 12 while His2516.52, Gln903.37, and Asn1865.42 were found as interacting (or in proximity) with the amide group of the 2-substituent of the same compound. Asn1865.42 appears as not directly interacting with the compounds of this study. On the other hand, a mutagenesis study has evidenced that the mutation of this residue to alanine leads to an increase of potency of both nucleoside and non-nucleoside derivatives (Thimm et al. 2013). The interaction between 3.37 and 5.42 residues is absent in the antagonist-bound A2AAR crystal structures but present in the agonist-bound 3QAK X-ray data (in the Ado- and NECA-bound A2AAR crystal structures the Gln893.37 is mutated to alanine), hence these residues could have a mechanistic role for the receptor function and could be not necessarily interaction points for ligands (Dal Ben et al. 2013).Figure 7


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 2 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

Fig7: Plot of interaction energies for residues belonging to the section 2 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 2 contains residues belonging to TM3 (Leu863.33, Thr893.36, Gln903.37, and Ile933.40), TM5 (Met1825.38, Asn1865.42, Cys1905.46, and Val1915.47), and TM6 (Trp2476.48 and His2516.52). These residues are involved in interaction with ribose group of nucleoside analogues (in particular the 4′-position) and with 2-substituent of non-nucleoside pyridine derivatives. Figure 7 represents the obtained results for section 2, again with blue and red versions corresponding to the 2YDO- and 3QAK-A2BAR models, respectively. The effect of the receptor residues for the interaction with ligands is comparable considering both nucleoside and non-nucleoside agonists. Firstly, Leu863.33 and Met1825.38 form a hydrophobic interaction with the ribose group of nucleosides and with the 2-substituent of pyridines. Secondly, it appears evident the contribution of Thr893.36 and His2516.52, in accordance with the results of superimposition experiments (see above). In particular, Thr893.36 provide a stabilizing effect for the polar hydrogen of NECAs 5′-amide group from 3–6, of thiomethylimidazole from 7–11, and of thioacetamide from 12. The effect of this residue is largely reduced in the case of the two Ado derivatives 1–2 that do not present a combination of H-bond acceptor and donor features at the 5′-position. His2516.52 cooperates with Thr893.36 in providing a stabilizing effect for ligands. In the case of non-nucleoside derivatives, it is interesting to notate the greater effect of this residue for 12 respect to 7–11 at both A2BAR models, suggesting a better interaction of His2516.52 for the amide function respect to an imidazole ring. The effect of the other residues of this section is not significant, with the exception in some cases of Gln903.37 (polar interaction with non-nucleoside derivatives in 3QAK-A2BAR model) and Trp2476.48. In a previous study (Sherbiny et al. 2009), Thr893.36 was suggested as interacting with 3-cyano substituent of 12 while His2516.52, Gln903.37, and Asn1865.42 were found as interacting (or in proximity) with the amide group of the 2-substituent of the same compound. Asn1865.42 appears as not directly interacting with the compounds of this study. On the other hand, a mutagenesis study has evidenced that the mutation of this residue to alanine leads to an increase of potency of both nucleoside and non-nucleoside derivatives (Thimm et al. 2013). The interaction between 3.37 and 5.42 residues is absent in the antagonist-bound A2AAR crystal structures but present in the agonist-bound 3QAK X-ray data (in the Ado- and NECA-bound A2AAR crystal structures the Gln893.37 is mutated to alanine), hence these residues could have a mechanistic role for the receptor function and could be not necessarily interaction points for ligands (Dal Ben et al. 2013).Figure 7

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.