Could the presence of sodium ion influence the accuracy and precision of the ligand-posing in the human A adenosine receptor orthosteric binding site using a molecular docking approach? Insights from Dockbench.

The allosteric modulation of G protein-coupled receptors (GPCRs) by sodium ions has received considerable attention as crystal structures of several receptors, in their inactive conformation, show a Na ion bound to specific residues which, in the human A adenosine receptor (hA AR), are Ser91, Trp246, Asn280, and Asn284. A cluster of water molecules completes the coordination of the sodium ion in the putative allosteric site. It is absolutely consolidated that the progress made in the field of GPCRs structural determination has increased the adoption of docking-driven approaches for the identification or the optimization of novel potent and selective ligands. Despite the extensive use of docking protocols in virtual screening approaches, to date, almost any of these studies have been carried out without taking into account the presence of the sodium cation and its first solvation shell in the putative allosteric binding site. In this study, we have focused our attention on determining how the presence of sodium ion binding and additionally its first hydration sphere, in hAAR could influence the ligand positioning accuracy during molecular docking simulations for most of the available resting and activated hA AR crystal structures, using DockBench as a comparative benchmarking tool and implementing a new correlation coefficient (EM). This work provides indications on the evidence that the posing performance (accuracy and/or precision) of the docking protocols in reproducing the crystallographic poses of different hA AR antagonists is generally increased in the presence of the sodium cation and its first solvation shell, in agreement with experimental observations. Consequently, the inclusion of sodium ion and its first solvation shell should be considered in order to facilitate the selection of new potential ligands in all molecular docking-based virtual screening protocols that aim to find novel GPCRs antagonists and inverse agonists.