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 1H 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.

Drug Screening in Human Cells by NMR Spectroscopy Allows the Early Assessment of Drug Potency / Luchinat E.; Barbieri L.; Cremonini M.; Nocentini A.; Supuran C.T.; Banci L.. - In: ANGEWANDTE CHEMIE. INTERNATIONAL EDITION. - ISSN 1433-7851. - ELETTRONICO. - 59:(2020), pp. 6535-6539. [10.1002/anie.201913436]

Drug Screening in Human Cells by NMR Spectroscopy Allows the Early Assessment of Drug Potency

Luchinat E.;Barbieri L.;Cremonini M.;Nocentini A.;Supuran C. T.;Banci L.
2020

Abstract

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 1H 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.
2020
59
6535
6539
Goal 3: Good health and well-being for people
Luchinat E.; Barbieri L.; Cremonini M.; Nocentini A.; Supuran C.T.; Banci L.
File in questo prodotto:
File Dimensione Formato  
Luchinat_et_al-2020-Angewandte_Chemie.pdf

accesso aperto

Descrizione: Articolo principale
Tipologia: Pdf editoriale (Version of record)
Licenza: Creative commons
Dimensione 1.97 MB
Formato Adobe PDF
1.97 MB Adobe PDF

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1199930
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 46
  • ???jsp.display-item.citation.isi??? 43
social impact