TY - JOUR
T1 - Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor
AU - Deganutti, Giuseppe
AU - Barkan, Kerry
AU - Preti, Barbara
AU - Leuenberger, Michele
AU - Wall, Mark
AU - Frenguelli, Bruno G
AU - Lochner, Martin
AU - Ladds, Graham
AU - Reynolds, Christopher A
N1 - 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 https://dx.doi.org/10.1021/acsptsci.0c00195
PY - 2021/2/12
Y1 - 2021/2/12
N2 - 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.
AB - 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.
KW - G protein coupled receptors
KW - GPCRs
KW - Adenosine A1 receptor
KW - A1R supervised molecular dynamics
KW - SuMD
KW - mutagenesis experiments
KW - binding
KW - Binding
KW - A R
KW - Mutagenesis experiments
KW - Supervised molecular dynamics
UR - http://www.scopus.com/inward/record.url?scp=85100246318&partnerID=8YFLogxK
U2 - 10.1021/acsptsci.0c00195
DO - 10.1021/acsptsci.0c00195
M3 - Article
C2 - 33615181
VL - 4
SP - 314
EP - 326
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
IS - 1
ER -