Ribose and Non-Ribose A2A Adenosine Receptor Agonists: Do They Share the Same Receptor Recognition Mechanism?

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.

“Dual Anta-Inhibitors” of the A2A Adenosine Receptor and Casein Kinase CK1delta: Synthesis, Biological Evaluation, and Molecular Modeling Studies

“…Indeed, the “dual anta-inhibitor”(compound 17 ) approaches the orthosteric site from the opposite side, establishing the first contact with the region comprised between the extracellular loops 1 and 3. Intriguingly, a similar behavior has recently been reported for the “non-ribose” partial agonist LUF5833 [ 48 ]. In the work of Bolcato et al, this binding pattern is exclusive to the “non-ribose” partial agonist LUF5833, in contrast with classic “ribose” agonists, which explore the same meta-binding site as compound 21 .…”

“…The remaining poses were then prioritized following the available structure-activity information for each receptor. Indeed, several studies have already been performed in the past by several academic and industrial groups about CK1δ and ARs, including us, and the most important features to guarantee stable binding with the receptors have been elucidated [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ].…”

“…SuMD is an enhanced-sampling method able to simulate the protein–ligand interaction pathway on a reduced timescale, exploiting a tabu-like supervision algorithm on the distance between the centers of mass of the ligand and the binding site, respectively [ 55 ]. Specifically, such a method has been successfully used on different targets in different scenarios [ 48 , 56 , 57 , 58 ]. To examine the dynamic aspects of the binding process between the most relevant ligands in our library, we executed SuMD simulations on both the CK1δ and A 2A AR proteins, taking as a reference the most potent molecule against CK1δ (compound 21 ) and the “dual anta-inhibitor” 17 .…”

Are Two Riboses Better Than One? The Case of the Recognition and Activation of Adenosine Receptors

“…Notably, the hydrogen bond between the exocyclic amine group of the adenine core of adenosine and the sidechain of Glu169 is replaced by analogous interactions portrayed by the N6‐linked ribose unit. Curiously, the interaction pattern of α‐FUR closely recalls the one that was recently described by Supervised Molecular Dynamics (SuMD) simulations for the non‐ribose agonist LUF5833: [34] as described in the original publication, the non‐ribose agonist can replace the required ribose‐involving interactions by stabilizing a network of water molecules. Despite the obvious difference in the ability to interact with the lower part of the binding site due to the lack/presence of the ribose moiety, the rest of the defining interaction features are practically superimposable, especially the lower importance of the interaction with Asn253 in stabilizing the bound complex.…”

Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma

“…One of the computational techniques able to capture these events is supervised molecular dynamics (SuMD) [ 40 ]. Indeed, this can be efficiently used to analyze the recognition pathway of small molecule ligands with a protein of interest, as already demonstrated in different scenarios on very distinct targets [ 41 , 42 , 43 , 44 ].…”