Computer aided comparative analysis of the binding modes of the adenosine receptor agonists for all known subtypes of adenosine receptors

Иванов, А. А.; Palyulin, V. A.; Зефиров, Н. С.

doi:10.1016/j.jmgm.2006.06.004

Cited by 25 publications

(45 citation statements)

References 64 publications

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“…Nevertheless, the lipophilic interactions of DPCPX presented here for the Rho-based A 1 AR are in consistence with most of the A 1 AR modeled previously. [104][105][106] Comparing the A 2A AR, it is worth to say that the model of b 2 -adrenergic-based A 2A AR showed the same binding ability for antagonists as the model described in ref. 61 as being the only one satisfying all the validation terms including the design and synthesis of new ligands which were active as it had been suggested by the model.…”

Section: Rhodopsin-based a 2a Ar Modelmentioning

confidence: 81%

Molecular modeling of A₁ and A_2A adenosine receptors: Comparison of rhodopsin‐ and β₂‐adrenergic‐based homology models through the docking studies

Yuzlenko¹,

Kieć‐Kononowicz²

2008

J Comput Chem

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Adenosine receptors (ARs) are members of the superfamily of G protein-coupled receptors. The homology models of adenosine A1 and A2A receptors were constructed. The high-resolution X-ray structure of bovine rhodopsin and crystal structure of beta2-adrenergic receptor were used as templates. The binding sites of the A1 and A2A ARs were constructed by using data obtained from mutagenesis experiments as well as docking simulations of the respective AR antagonsists DPCPX and XAC. To compare rhodopsin- and beta2-adrenergic-based models, the binding mode of A1 (KW-3902, LUF-5437) and A2A (KW-6002, ZM-241385) ARs antagonists were also examined. The differences in the binding ability of both models were noted during the study. The beta2-adrenergic-based A2A AR model was much more capable to stabilize the ligand in the binding site cavity than the corresponding rhodopsin-based A2A AR model, however, such differences were not so clear in case of A1 AR models. It was suggested that for the A1 AR it is possible to use the crystal structure of rhodopsin as a template as well as beta2-adrenergic receptor, but for A2A AR, with the now available beta2-adrenergic receptor X-ray structure, docking studies should be avoided on the rhodopsin-based model. However, taking into account that the beta2AR shares about 31% of the residues with the AR in comparison to 21% in case of bRho, we suggest using beta2-adrenergic-based models for the A1 and A2A ARs for further in silico ligand screening also because of their generally better ability to stabilize ligands inside the binding pocket.

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Section: Rhodopsin-based a 2a Ar Modelmentioning

confidence: 81%

Molecular modeling of A₁ and A_2A adenosine receptors: Comparison of rhodopsin‐ and β₂‐adrenergic‐based homology models through the docking studies

Yuzlenko¹,

Kieć‐Kononowicz²

2008

J Comput Chem

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“…Since the location of the binding site of ligands in the complex has been known by site-directed mutagenesis (Olah et al, 1992;Kim et al, 1995;Gao et al, 2000;Fredholm et al, 2001;Dawson and Wells, 2001;Giordanetto et al, 2003;Gutierrez-de-Teran et al, 2004;Ivanov et al, 2007;Piirainen et al, 2011;Kolb et al, 2012), the grid box was centered on amino nitrogen of His278. Grid box dimension was 60 9 60 9 60 with a 0.375 Å grid point spacing.…”

Section: Docking Simulationmentioning

confidence: 99%

“…Likewise, Tuccinardi et al (2006) reported 3D models of the A 1 and A 2A AR constructed by means of a homology procedure, using bovine rhodopsin as a template. The 3D models of the whole structure of known AR subtypes have been made and described by Ivanov et al (2007). These models have been used for molecular docking of the native agonist, adenosine, and 46 adenosine derivatives (Ivanov et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…The 3D models of the whole structure of known AR subtypes have been made and described by Ivanov et al (2007). These models have been used for molecular docking of the native agonist, adenosine, and 46 adenosine derivatives (Ivanov et al, 2007). The recently published crystal structure of the human A 2A , sharing 51 % identity with human A 1 , in complex with the high-affinity antagonist ZM-241385, provides a new template for A 1 modeling (Jaakola et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Insights into the human A1 adenosine receptor from molecular dynamics simulation: structural study in the presence of lipid membrane

et al. 2015

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Homology modeling, molecular docking and molecular dynamics (MD) simulation methods were used to build a reliable model for A 1 AR (as one of the G protein-coupled receptors-GPCRs) and to explore the structural features and binding mechanism of ligands to this receptor. A model of A 1 AR was built and inserted in a hydrated lipid bilayer, and 20-ns MD simulation was performed to examine the stability of the best model. In this study, RG-14718 as the best A 1 AR agonist and bamifylline as a selective antagonist of A 1 AR have been docked into the active site of the A 1 AR. After docking, two 20-ns MD simulation was performed on the A 1 ARligand complex to explore effects of the presence of lipid membrane in the vicinity of the A 1 AR-ligand complex. At the end of the MD simulation, a change in the position and orientation of the ligand in the binding site was observed. This important observation indicated that the application of MD simulation after docking of ligands is useful. Thr270, His278 and Asn70 were crucial residues for hydrogen bonds with these ligands. Phe171, Glu172, Tyr271 and Ile274 were determined to be involved in ligand-receptor binding. The results obtained are in good agreement with most of the site-directed mutagenesis data reported by others. Our results show that molecular modeling and rational drug design for adenosine targets is a possible approach.

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“…The 5′-methylcarboxamido analogue of (R,S)-PHPNECA ((R,S)-PHPMECA, 38) was 4.5-fold less active than the parent compound (hA 2B EC 50 =5.0 μM) [74]. A computational molecular docking of an heterogeneous set of 46 known adenosine-like AR agonists, based on the molecular models of the 3D structure of the four known AR subtypes, was recently performed [84]. Comparison between the putative ligand-receptor complexes for each receptor subtype suggested a general agonist-binding mode, along with possible explanations for the differences in agonist activities and AR selectivities.…”

Section: Adenosine-like Ligandsmentioning

confidence: 99%

Recent improvements in the development of A2B adenosine receptor agonists

Baraldi

Tabrizi²,

Fruttarolo³

et al. 2009

Purinergic Signalling

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Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A 1 , A 2A , A 2B and A 3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A 2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A 2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A 2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleosidebased agonists are the result of modifying adenosine by substitution at the N 6 -, C 2 -positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-and its 2-chloro analogue 23 (hA 1 K i =3500 nM, hA 2A K i = 4950 nM, hA 2B EC 50 =210 nM, hA 3 K i >5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA 2B AR.Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3, 5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60-6583, hA 1 , hA 2A , hA 3 EC 50 >10 μM; hA 2B EC 50 =3 nM) is currently under preclinicalphase investigation for treating coronary artery disorders and atherosclerosis.

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Computer aided comparative analysis of the binding modes of the adenosine receptor agonists for all known subtypes of adenosine receptors

Cited by 25 publications

References 64 publications

Molecular modeling of A₁ and A_2A adenosine receptors: Comparison of rhodopsin‐ and β₂‐adrenergic‐based homology models through the docking studies

Molecular modeling of A₁ and A_2A adenosine receptors: Comparison of rhodopsin‐ and β₂‐adrenergic‐based homology models through the docking studies

Insights into the human A1 adenosine receptor from molecular dynamics simulation: structural study in the presence of lipid membrane

Recent improvements in the development of A2B adenosine receptor agonists

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Computer aided comparative analysis of the binding modes of the adenosine receptor agonists for all known subtypes of adenosine receptors

Cited by 25 publications

References 64 publications

Molecular modeling of A1 and A2A adenosine receptors: Comparison of rhodopsin‐ and β2‐adrenergic‐based homology models through the docking studies

Molecular modeling of A1 and A2A adenosine receptors: Comparison of rhodopsin‐ and β2‐adrenergic‐based homology models through the docking studies

Insights into the human A1 adenosine receptor from molecular dynamics simulation: structural study in the presence of lipid membrane

Recent improvements in the development of A2B adenosine receptor agonists

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Product

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About

Molecular modeling of A₁ and A_2A adenosine receptors: Comparison of rhodopsin‐ and β₂‐adrenergic‐based homology models through the docking studies

Molecular modeling of A₁ and A_2A adenosine receptors: Comparison of rhodopsin‐ and β₂‐adrenergic‐based homology models through the docking studies