Identification of V6.51L as a selectivity hotspot in stereoselective A2B adenosine receptor antagonist recognition

Abstract The four adenosine receptors (ARs) A1AR, A2AAR, A2BAR, and A3AR are G protein-coupled receptors (GPCRs) for which an exceptional amount of experimental and structural data is available. Still, limited success has been achieved in getting new chemical modulators on the market. As such, there...

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Autores principales:	Xuesong Wang, Willem Jespers, Rubén Prieto-Díaz, Maria Majellaro, Adriaan P. IJzerman, Gerard J. P. van Westen, Eddy Sotelo, Laura H. Heitman, Hugo Gutiérrez-de-Terán
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e3d7468f1f4048819ea81f585f212118
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spelling	oai:doaj.org-article:e3d7468f1f4048819ea81f585f2121182021-12-02T16:15:05ZIdentification of V6.51L as a selectivity hotspot in stereoselective A2B adenosine receptor antagonist recognition10.1038/s41598-021-93419-x2045-2322https://doaj.org/article/e3d7468f1f4048819ea81f585f2121182021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93419-xhttps://doaj.org/toc/2045-2322Abstract The four adenosine receptors (ARs) A1AR, A2AAR, A2BAR, and A3AR are G protein-coupled receptors (GPCRs) for which an exceptional amount of experimental and structural data is available. Still, limited success has been achieved in getting new chemical modulators on the market. As such, there is a clear interest in the design of novel selective chemical entities for this family of receptors. In this work, we investigate the selective recognition of ISAM-140, a recently reported A2BAR reference antagonist. A combination of semipreparative chiral HPLC, circular dichroism and X-ray crystallography was used to separate and unequivocally assign the configuration of each enantiomer. Subsequently affinity evaluation for both A2A and A2B receptors demonstrate the stereospecific and selective recognition of (S)-ISAM140 to the A2BAR. The molecular modeling suggested that the structural determinants of this selectivity profile would be residue V2506.51 in A2BAR, which is a leucine in all other ARs including the closely related A2AAR. This was herein confirmed by radioligand binding assays and rigorous free energy perturbation (FEP) calculations performed on the L249V6.51 mutant A2AAR receptor. Taken together, this study provides further insights in the binding mode of these A2BAR antagonists, paving the way for future ligand optimization.Xuesong WangWillem JespersRubén Prieto-DíazMaria MajellaroAdriaan P. IJzermanGerard J. P. van WestenEddy SoteloLaura H. HeitmanHugo Gutiérrez-de-TeránNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xuesong Wang Willem Jespers Rubén Prieto-Díaz Maria Majellaro Adriaan P. IJzerman Gerard J. P. van Westen Eddy Sotelo Laura H. Heitman Hugo Gutiérrez-de-Terán Identification of V6.51L as a selectivity hotspot in stereoselective A2B adenosine receptor antagonist recognition
description	Abstract The four adenosine receptors (ARs) A1AR, A2AAR, A2BAR, and A3AR are G protein-coupled receptors (GPCRs) for which an exceptional amount of experimental and structural data is available. Still, limited success has been achieved in getting new chemical modulators on the market. As such, there is a clear interest in the design of novel selective chemical entities for this family of receptors. In this work, we investigate the selective recognition of ISAM-140, a recently reported A2BAR reference antagonist. A combination of semipreparative chiral HPLC, circular dichroism and X-ray crystallography was used to separate and unequivocally assign the configuration of each enantiomer. Subsequently affinity evaluation for both A2A and A2B receptors demonstrate the stereospecific and selective recognition of (S)-ISAM140 to the A2BAR. The molecular modeling suggested that the structural determinants of this selectivity profile would be residue V2506.51 in A2BAR, which is a leucine in all other ARs including the closely related A2AAR. This was herein confirmed by radioligand binding assays and rigorous free energy perturbation (FEP) calculations performed on the L249V6.51 mutant A2AAR receptor. Taken together, this study provides further insights in the binding mode of these A2BAR antagonists, paving the way for future ligand optimization.
format	article
author	Xuesong Wang Willem Jespers Rubén Prieto-Díaz Maria Majellaro Adriaan P. IJzerman Gerard J. P. van Westen Eddy Sotelo Laura H. Heitman Hugo Gutiérrez-de-Terán
author_facet	Xuesong Wang Willem Jespers Rubén Prieto-Díaz Maria Majellaro Adriaan P. IJzerman Gerard J. P. van Westen Eddy Sotelo Laura H. Heitman Hugo Gutiérrez-de-Terán
author_sort	Xuesong Wang
title	Identification of V6.51L as a selectivity hotspot in stereoselective A2B adenosine receptor antagonist recognition
title_short	Identification of V6.51L as a selectivity hotspot in stereoselective A2B adenosine receptor antagonist recognition
title_full	Identification of V6.51L as a selectivity hotspot in stereoselective A2B adenosine receptor antagonist recognition
title_fullStr	Identification of V6.51L as a selectivity hotspot in stereoselective A2B adenosine receptor antagonist recognition
title_full_unstemmed	Identification of V6.51L as a selectivity hotspot in stereoselective A2B adenosine receptor antagonist recognition
title_sort	identification of v6.51l as a selectivity hotspot in stereoselective a2b adenosine receptor antagonist recognition
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e3d7468f1f4048819ea81f585f212118
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Identification of V6.51L as a selectivity hotspot in stereoselective A2B adenosine receptor antagonist recognition

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