Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor

Giuseppe Deganutti, Kerry Barkan, Barbara Preti, Michele Leuenberger, Mark Wall, Bruno G Frenguelli, Martin Lochner, Graham Ladds, Christopher A Reynolds

    Research output: Contribution to journalArticlepeer-review

    6 Citations (Scopus)
    47 Downloads (Pure)


    Despite being among the most characterized G protein-coupled receptors (GPCRs), adenosine receptors (ARs) have always been a difficult target in drug design. To date, no agonist other than the natural effector and the diagnostic regadenoson has been approved for human use. Recently, the structure of the adenosine A1 receptor (A1R) was determined in the active, Gi protein complexed state; this has important repercussions for structure-based drug design. Here, we employed supervised molecular dynamics simulations and mutagenesis experiments to extend the structural knowledge of the binding of selective agonists to A1R. Our results identify new residues involved in the association and dissociation pathway, they suggest the binding mode of N6-cyclopentyladenosine (CPA) related ligands, and they highlight the dramatic effect that chemical modifications can have on the overall binding mechanism, paving the way for the rational development of a structure-kinetics relationship of A1R agonists.

    Original languageEnglish
    Pages (from-to)314-326
    Number of pages13
    JournalACS Pharmacology and Translational Science
    Issue number1
    Early online date20 Jan 2021
    Publication statusPublished - 12 Feb 2021

    Bibliographical note

    This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Pharmacology and Translational Science, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see


    Leverhulme Trust (Grant RPG-2017-255, C.A.R. and G.L. to fund K.B. and G.D.)


    • G protein coupled receptors
    • GPCRs
    • Adenosine A1 receptor
    • A1R supervised molecular dynamics
    • SuMD
    • mutagenesis experiments
    • binding
    • Binding
    • A R
    • Mutagenesis experiments
    • Supervised molecular dynamics

    ASJC Scopus subject areas

    • Pharmacology (medical)
    • Pharmacology


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