Journal
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
Volume 4, Issue 1, Pages 314-326Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsptsci.0c00195
Keywords
G protein coupled receptors; GPCRs; adenosine A1 receptor; A(1)R; supervised molecular dynamics; SuMD; mutagenesis experiments; binding
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Funding
- Royal Society Industry Fellowship
- Leverhulme Trust [RPG-2017-255]
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This study extended the structural knowledge of the binding of selective agonists to A(1)R through supervised molecular dynamics simulations and mutagenesis experiments, identifying new residues involved in the association and dissociation pathway, proposing the binding mode of N-6-cyclopentyladenosine (CPA) related ligands, and highlighting the significant effect of chemical modifications on the overall binding mechanism.
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 (A(1)R) was determined in the active, G(i) 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 A(1)R. Our results identify new residues involved in the association and dissociation pathway, they suggest the binding mode of N-6-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 A(1)R agonists.
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