posted on 2021-01-21, 07:45authored byGiuseppe Deganutti, Kerry Barkan, Barbara Preti, Michele Leuenberger, Mark Wall, Bruno G. Frenguelli, Martin Lochner, Graham Ladds, Christopher A. Reynolds
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.