上海科技大学知识管理系统

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. © 2023 American Chemical Society.