Drug Screening in Human Cells by NMR Spectroscopy Allows the Early Assessment of Drug Potency.
Angew Chem Int Ed Engl
; 59(16): 6535-6539, 2020 04 16.
Article
em En
| MEDLINE
| ID: mdl-32022355
ABSTRACT
Structure-based drug development is often hampered by the lack of inâ
vivo activity of promising compounds screened inâ
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 1 Hâ
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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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Preparações Farmacêuticas
/
Espectroscopia de Ressonância Magnética
/
Desenho de Fármacos
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article