Abstract
Adenosine receptors have been a promising class of targets for the development of new therapies for several diseases. In recent years, a renewed interest in this field has risen, thanks to the implementation of a novel class of agonists that lack the ribose moiety, once considered essential for the agonistic profile. Recently, an X-ray crystal structure of the A2A adenosine receptor has been solved, providing insights about the receptor activation from this novel class of agonists. Starting from this structural information, we have performed supervised molecular dynamics (SuMD) simulations to investigate the binding pathway of a non-nucleoside adenosine receptor agonist as well as one of three classic agonists. Furthermore, we analyzed the possible role of water molecules in receptor activation.
Highlights
Adenosine Receptor Agonists: DoAdenosine is the endogenous agonist of a group of class A G protein-coupled receptors (GPCRs) named adenosine receptors (AR); four receptors belong to this family: A1, A2A, A2B, and A3
While this novel class of AR agonists presents several advantages over classic adenosine-derived ligands, the AR. Activation for this class of compounds has been difficult to understand since they lack the ribose moiety, which was considered essential for the agonistic profile of AR ligands [12]
From a methodological point of view, one main limitation of the supervised molecular dynamics (SuMD) technique, as is the case for traditional molecular dynamics (MD), is the fact that simulations are carried out assuming fixed protonation states
Summary
Adenosine is the endogenous agonist of a group of class A G protein-coupled receptors (GPCRs) named adenosine receptors (AR); four receptors belong to this family: A1 , A2A , A2B , and A3. Progress was made in the field of AR agonists as therapeutic agents [10] with the publication by Bayer of some patents regarding non-nucleoside AR agonists [11] While this novel class of AR agonists presents several advantages over classic adenosine-derived ligands (easier synthesis, improved pharmacokinetics, and oral bioavailability), the AR activation for this class of compounds has been difficult to understand since they lack the ribose moiety, which was considered essential for the agonistic profile of AR ligands [12].
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