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Adenosine A2A Receptor (A2AAR) Ligand Screening Using the 19F-NMR Probe FPPA
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    Adenosine A2A Receptor (A2AAR) Ligand Screening Using the 19F-NMR Probe FPPA
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    • Jinfeng Zhang
      Jinfeng Zhang
      iHuman Institute, ShanghaiTech University, Shanghai 201210, China
      School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
    • Dandan Feng
      Dandan Feng
      iHuman Institute, ShanghaiTech University, Shanghai 201210, China
      School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
      More by Dandan Feng
    • Jianjun Cheng*
      Jianjun Cheng
      iHuman Institute, ShanghaiTech University, Shanghai 201210, China
      School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
      *Email: [email protected]
    • Kurt Wüthrich*
      Kurt Wüthrich
      iHuman Institute, ShanghaiTech University, Shanghai 201210, China
      Department of Integrated Structural and Computational Biology, Scripps Research, La Jolla, California 92037, United States
      Institute of Molecular Biology and Biophysics, ETH Zürich, 8093 Zürich, Switzerland
      *Email: [email protected]; [email protected]
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2023, 145, 28, 15061–15064
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    https://doi.org/10.1021/jacs.3c04218
    Published June 5, 2023
    Copyright © 2023 American Chemical Society

    Abstract

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    The binding affinity of G protein-coupled receptor (GPCR) ligands is customarily measured by radio-ligand competition experiments. As an alternative approach, 19F nuclear magnetic resonance spectroscopy (19F-NMR) is used for the screening of small-molecule lead compounds in drug discovery; the two methods are complementary in that the measurements are performed with widely different experimental conditions. Here, we used the structure of the A2A adenosine receptor (A2AAR) complex with V-2006 (3-(4-amino-3-methylbenzyl)-7-(furan-2-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine) as the basis for the design of a fluorine-containing probe molecule, FPPA (4-(furan-2-yl)-7-(4-(trifluoromethyl)benzyl)-7H-pyrrolo[2,3-d]pyramidin-2-amine), for binding studies with A2AAR. A protocol of experimental conditions for drug screening and measurements of drug binding affinities using 1D 19F-NMR observation of FPPA is validated with studies of known A2AAR ligands. 19F-NMR with FPPA is thus found to be a robust approach for the discovery of ligands with new core structures, which will expand the libraries of A2AAR-targeting drug candidates.

    Copyright © 2023 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c04218.

    • Reaction optimization, detailed mechanistic evaluation, experimental procedures, characterization data, copies of NMR spectra, and HRMS and HPLC traces of both products (PDF)

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    This article is cited by 3 publications.

    1. Qingxin Li, CongBao Kang. Perspectives on Applications of 19F-NMR in Fragment-Based Drug Discovery. Molecules 2024, 29 (23) , 5748. https://doi.org/10.3390/molecules29235748
    2. R. Andrew Atkinson. NMR of proteins and nucleic acids. 2024, 206-230. https://doi.org/10.1039/9781837675630-00206
    3. Canyong Guo, Lingyun Yang, Zhijun Liu, Dongsheng Liu, Kurt Wüthrich. Two-Dimensional NMR Spectroscopy of the G Protein-Coupled Receptor A2AAR in Lipid Nanodiscs. Molecules 2023, 28 (14) , 5419. https://doi.org/10.3390/molecules28145419

    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2023, 145, 28, 15061–15064
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.3c04218
    Published June 5, 2023
    Copyright © 2023 American Chemical Society

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