Simulation and Comparative Analysis of Different Binding Modes of Non‐nucleoside Agonists at the A_2AAdenosine Receptor

Abstract

Non-nucleoside agonists of adenosine receptors were analysed at the A2A adenosine receptor to simulate and compare their possible binding modes. The docking studies were performed by using different arrangements of the binding cavity and various docking tools. Mutagenesis results reported in literature were used as reference data for the assessment of the different ligand arrangements observed in this study. The results suggest four possible binding modes, two of which appear compatible with an agonist activity and in agreement with the mutagenesis data. This study provides useful information for the design of new simplified compounds presenting agonist activity at the A2A adenosine receptor.

Amino-3,5-Dicyanopyridines Targeting the Adenosine Receptors. Ranging from Pan Ligands to Combined A1/A2B Partial Agonists

“…The simulated binding mode at both the hA 1 and hA 2B AR structures, generally associated to the best score, presents the herein reported compounds oriented similarly to analogous derivatives previously reported as hAR ligands (Figure 2A) [12,35,36]. In detail, the pyridine scaffold is located in the AR cavity in correspondence to the purine moiety of Ado observed at the hA 1 AR cryo-EM structure and at the hA 2A AR template, and interacts with the side chains of hA 1 AR residues Phe171 extracellular loop (EL) 2 and Ile274 7.39 (Phe173 and Ile276 7.39 in hA 2B AR).…”

Non-Nucleoside Agonists of the Adenosine Receptors: An Overview

“…However, this arrangement appears possible only for derivatives presenting a small thioarylalkyl group. A further docking conformation was observed at the A 2A AR for the Otsuka Pharmaceutical pyrimidine-based agonists (Figure 8b) [109]. This conformation is an upside-down version of the general binding mode described above, with the thioarylalkyl group externally located and the phenyl ring in the depth of the cavity.…”

“…However, this arrangement appears possible only for derivatives presenting a small thioarylalkyl group. A further docking conformation was observed at the A2AAR for the Otsuka Pharmaceutical pyrimidine-based agonists (Figure 8b) [109]. This conformation is an upside- This docking conformation makes the heterocyclic core still be located in the center of the binding cavity, but the phenyl ring directly linked to it points toward the extracellular environment, while the thioarylalkyl chain is inserted in the depth of the cavity.…”

“…These works suggested different ligand-receptor recognition patterns for these two families of AR agonists. Molecular modelling studies were hence performed to interpret these data and to simulate the potential non-nucleoside agonist conformations within the AR binding cavity [36,37,63,64,68,[106][107][108][109].…”

“…These works suggested different ligand-receptor recognition patterns for these two families of AR agonists. Molecular modelling studies were hence performed to interpret these data and to simulate the potential non-nucleoside agonist conformations within the AR binding cavity [36,37,63,64,68,[106][107][108][109]. The docking conformation suggested by the majority of modelling studies presents the purine/pyrimidine scaffold of the agonists positioned analogously to the purine core of the nucleoside agonists (X-Ray/cryo-EM data), between a conserved phenylalanine in the extracellular loop (EL) 2 (i.e., Phe171 in the A1AR) and a conserved isoleucine in the transmembrane (TM) chain 7 (position 7.39 according to the Ballesteros and Weinstein numbering system [110]; in the A1AR, this position is occupied by Ile274 [111]).…”