X‐Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists
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|Title:||X‐Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists
Azuaje Guerrero, Jhonny Alberto
García Mera, Xerardo Xusto
De Graaf, Chris
Doré, Andrew S.
Mason, Jonathan S.
Cooke, Robert M.
Sotelo Pérez, Eddy
Gutiérrez de Terán, Hugo
|Affiliation:||Universidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares
Universidade de Santiago de Compostela. Departamento de Química Orgánica
|Subject:||Adenosine receptors | Biophysical mapping (BPM) | Free energy perturbation (FEP) | G protein-coupled receptor (GPCR) ||
|Date of Issue:||2020
|Citation:||W. Jespers, G. Verdon, J. Azuaje, M. Majellaro, H. Keränen, X. García-Mera, M. Congreve, F. Deflorian, C. de Graaf, A. Zhukov, A. S. Doré, J. S. Mason, J. Åqvist, R. M. Cooke, E. Sotelo, H. Gutiérrez-de-Terán, Angew. Chem. Int. Ed. 2020, 59, 16536
|Abstract:||We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X‐ray crystallography to reveal the binding mode of an antagonist series to the A2A adenosine receptor (AR). Eight A2AAR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A2AAR were experimentally determined and investigated through a cycle of ligand‐FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X‐ray crystallography of the A2AAR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A2AAR, an emerging target in immuno‐oncology|
|Rights:||© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co.KGaA. This is an open access article under the terms of the CreativeCommons AttributionLicense, which permits use, distribution and reproduction in any medium, provided the original work is properly cited
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Except where otherwise noted, this item's license is described as © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co.KGaA. This is an open access article under the terms of the CreativeCommons AttributionLicense, which permits use, distribution and reproduction in any medium, provided the original work is properly cited