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Could the presence of sodium ion influence the accuracy and precision of the ligand-posing in the human A2A adenosine receptor orthosteric binding site using a molecular docking approach? Insights from Dockbench

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Abstract

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 A2A adenosine receptor (hA2A AR), are Ser913.39, Trp2466.48, Asn2807.45, and Asn2847.49. 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 hA2AAR could influence the ligand positioning accuracy during molecular docking simulations for most of the available resting and activated hA2A 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 hA2A 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.

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Acknowledgements

MMS lab is very grateful to Chemical Computing Group and OpenEye for the scientific and technical partnership. MMS lab gratefully acknowledges the support of NVIDIA Corporation with the donation of the Titan Xp GPU used for this research.

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Authors and Affiliations

  1. Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131, Padova, Italy

    Enrico Margiotta, Giuseppe Deganutti & Stefano Moro

  2. School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, CO4 3SQ, UK

    Giuseppe Deganutti

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  1. Enrico Margiotta
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  2. Giuseppe Deganutti
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Correspondence to Stefano Moro.

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Margiotta, E., Deganutti, G. & Moro, S. Could the presence of sodium ion influence the accuracy and precision of the ligand-posing in the human A2A adenosine receptor orthosteric binding site using a molecular docking approach? Insights from Dockbench. J Comput Aided Mol Des 32, 1337–1346 (2018). https://doi.org/10.1007/s10822-018-0174-2

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  • DOI: https://doi.org/10.1007/s10822-018-0174-2

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