ArticleJournal of molecular graphics & modelling2006
Docking studies of agonists and antagonists suggest an activation pathway of the A3 adenosine receptor.
Article in Journal of molecular graphics & modelling, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 44 citations in OpenAlex.
- 4'-Thionucleosides as adenosine AMedicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Review
- In Silico Drug Design for Purinergic GPCRs: Overview on Molecular Dynamics Applied to Adenosine and P2Y Receptors.Biomolecules · 2020Review
- AJournal of computer-aided molecular design · 2019Article
- Breakthrough in GPCR Crystallography and Its Impact on Computer-Aided Drug Design.Methods in molecular biology (Clifton, N.J.) · 2018Article
- Steered molecular dynamics simulation of the binding of the bovine auxilin J domain to the Hsc70 nucleotide-binding domain.Journal of molecular modeling · 2017Article
- NJournal of medicinal chemistry · 2017Article
- Structural Probing and Molecular Modeling of the A₃ Adenosine Receptor: A Focus on Agonist Binding.Molecules (Basel, Switzerland) · 2017Review
- Topological sub-structural molecular design (TOPS-MODE): a useful tool to explore key fragments of human A3 adenosine receptor ligands.Molecular diversity · 2016Article
- Molecular Determinants of CGS21680 Binding to the Human Adenosine A2A Receptor.Molecular pharmacology · 2015Article
- Predicted structures of agonist and antagonist bound complexes of adenosine A3 receptor.Proteins · 2011Article
- Predicted structures and dynamics for agonists and antagonists bound to serotonin 5-HT2B and 5-HT2C receptors.Journal of chemical information and modeling · 2011Article
- Design, synthesis, and binding of homologated truncated 4'-thioadenosine derivatives at the human A3 adenosine receptors.Bioorganic & medicinal chemistry · 2010Article
- Medicinal chemistry of the A3 adenosine receptor: agonists, antagonists, and receptor engineering.Handbook of experimental pharmacology · 2009Review
- Structure-activity relationships of truncated D- and l-4'-thioadenosine derivatives as species-independent A3 adenosine receptor antagonists.Journal of medicinal chemistry · 2008Article
- Selective A(3) adenosine receptor antagonists derived from nucleosides containing a bicyclo[3.1.0]hexane ring system.Bioorganic & medicinal chemistry · 2008Article
- Probing distal regions of the A2B adenosine receptor by quantitative structure-activity relationship modeling of known and novel agonists.Journal of medicinal chemistry · 2008Article
- Neoceptors: reengineering GPCRs to recognize tailored ligands.Trends in pharmacological sciences · 2007Review
- Action of nucleosides and nucleotides at 7 transmembrane-spanning receptors.Nucleosides, nucleotides & nucleic acids · 2006Review
- Three-dimensional quantitative structure-activity relationship of nucleosides acting at the A3 adenosine receptor: analysis of binding and relative efficacy.Journal of chemical information and modelingArticle
- Synthesis and Binding Affinity of Homologated Adenosine Analogues as ABulletin of the Korean Chemical SocietyArticle
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
Structural determinants of ligand efficacy in the human A(3) adenosine receptor (AR) were studied using pharmacophore and docking analyses of various categories of A(3) selective ligands: inverse agonist, neutral antagonist (nonnucleoside and nucleoside), and agonist (partial and full). The homology modeling of GPCRs was adapted to provide two templates: the rhodopsin-based resting state for antagonist binding and a putative Meta I state, conformationally altered at a key residue (W6.48), for agonist binding. The preferential binding domains and/or local conformational changes associated with docking of three high affinity A(3)AR ligands were compared: inverse agonist PSB-11 1 ((R)-8-ethyl-4-methyl-2-phenyl-imidazo[2,1-i]purin-5-one); neutral antagonist MRE-3008F20 7 (5-[[(4-methoxyphenyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)pyra-zolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine), and full agonist Cl-IB-MECA 21 (2-chloro-N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine) to define a distinct recognition mode for each. Ribose-containing agonists were more hydrophilic than nonnucleoside antagonists, and H-bonding ability at the ribose 3'- and 5'-positions was required for agonism. From the receptor perspective, common requirements for activation included the destabilization of H-bond networks at W6.48 and H7.43, the specific interactions of the ribose moiety in its putative hydrophilic pocket at T3.36, S7.42, and H7.43, the stabilization of the complex by inward movement of F5.43, and the characteristic rotation of W6.48. By analogy, outward rotation of the W6.48 side-chain upon activation of an internally-crosslinking mutant M(3) muscarinic receptor was indicated by constrained molecular dynamics (MD). Our results are consistent with an anti-clockwise rotation (from the extracellular view) of transmembrane domains 3, 5, 6, and 7, as proposed for other Family A GPCRs. Thus, the putative conformational changes associated with A(3)AR activation indicate a shared mechanism of GPCR activation similar to rhodopsin.
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