Adenosine A2A Receptor (A2AAR) Ligand Screening Using the 19F-NMR Probe FPPAClick to copy article linkArticle link copied!
- Jinfeng ZhangJinfeng ZhangiHuman Institute, ShanghaiTech University, Shanghai 201210, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaMore by Jinfeng Zhang
- Dandan FengDandan FengiHuman Institute, ShanghaiTech University, Shanghai 201210, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaMore by Dandan Feng
- Jianjun Cheng*Jianjun Cheng*Email: [email protected]iHuman Institute, ShanghaiTech University, Shanghai 201210, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaMore by Jianjun Cheng
- Kurt Wüthrich*Kurt Wüthrich*Email: [email protected]; [email protected]iHuman Institute, ShanghaiTech University, Shanghai 201210, ChinaDepartment of Integrated Structural and Computational Biology, Scripps Research, La Jolla, California 92037, United StatesInstitute of Molecular Biology and Biophysics, ETH Zürich, 8093 Zürich, SwitzerlandMore by Kurt Wüthrich
Abstract

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.
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This article is cited by 3 publications.
- Qingxin Li, CongBao Kang. Perspectives on Applications of 19F-NMR in Fragment-Based Drug Discovery. Molecules 2024, 29
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, 5748. https://doi.org/10.3390/molecules29235748
- R. Andrew Atkinson. NMR of proteins and nucleic acids. 2024, 206-230. https://doi.org/10.1039/9781837675630-00206
- 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
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, 5419. https://doi.org/10.3390/molecules28145419
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