Identification of V6.51L as a selectivity hotspot in stereoselective A(2B) adenosine receptor antagonist recognition
| Autor: | María Majellaro, Xuesong Wang, Willem Jespers, Adriaan P. IJzerman, Hugo Gutiérrez-de-Terán, Rubén Prieto-Díaz, Gerard J. P. van Westen, Eddy Sotelo, Laura H Heitman |
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| Přispěvatelé: | Universidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares, Universidade de Santiago de Compostela. Departamento de Química Orgánica |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Circular dichroism
Computational chemistry Molecular model Stereochemistry Science Pharmacology and Toxicology Adenosine receptor antagonist 01 natural sciences 03 medical and health sciences G protein-coupled receptors Receptor pharmacology Receptor 030304 developmental biology G protein-coupled receptor 0303 health sciences Lead optimization Multidisciplinary 010405 organic chemistry Chemistry Ligand (biochemistry) Farmakologi och toxikologi Adenosine receptor 0104 chemical sciences Medicine Enantiomer |
| Zdroj: | Minerva: Repositorio Institucional de la Universidad de Santiago de Compostela Universidad de Santiago de Compostela (USC) Scientific Reports Scientific Reports, Vol 11, Iss 1, Pp 1-10 (2021) Scientific Reports, 11. Springer Science and Business Media LLC Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela instname |
| Popis: | 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 This work was financially supported by the Consellería de Cultura, Educacioń e Ordenacioń Universitaria of the Galician Government: (grant: ED431B2017/70), Centro singular de Investigacioń de Galicia accreditation 2016−2019 (ED431G/ 09), Xunta de Galicia (ED431C 2018/21) and the European Regional Development Fund (ERDF). Xuesong Wang thanks the China Scholarship Council (CSC) for her PhD scholarship. The authors are part of the EU COST action ERNEST (CA 18133) and the Swedish strategic research program eSSENCE (H.G.dT., W.J.) SI |
| Databáze: | OpenAIRE |
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