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


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)(In-Press)
Number of pages13
JournalACS Pharmacology & Translational Science
Early online date20 Jan 2021
Publication statusE-pub ahead of print - 20 Jan 2021


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


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

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

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