期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 59, 期 16, 页码 6535-6539出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201913436
关键词
drug design; drug screening; in-cell NMR spectroscopy; structural biology; sulfonamide
资金
- iNEXT - Horizon 2020 programme of the European Commission [653706]
- Instruct-ULTRA, an EU H2020 project [731005]
Structure-based drug development is often hampered by the lack of in vivo activity of promising compounds screened in vitro, due to low membrane permeability or poor intracellular binding selectivity. Herein, we show that ligand screening can be performed in living human cells by intracellular protein-observed NMR spectroscopy, without requiring enzymatic activity measurements or other cellular assays. Quantitative binding information is obtained by fast, inexpensive H-1 NMR experiments, providing intracellular dose- and time-dependent ligand binding curves, from which kinetic and thermodynamic parameters linked to cell permeability and binding affinity and selectivity are obtained. The approach was applied to carbonic anhydrase and, in principle, can be extended to any NMR-observable intracellular target. The results obtained are directly related to the potency of candidate drugs, that is, the required dose. The application of this approach at an early stage of the drug design pipeline could greatly increase the low success rate of modern drug development.
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