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Drug Screening Boosted by Hyperpolarized Long‐Lived States in NMR |
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| Authors: | Roberto Buratto Aurélien Bornet Jonas Milani Daniele Mammoli Basile Vuichoud Dr Nicola Salvi Maninder Singh Aurélien Laguerre Dr Solène Passemard Dr Sandrine Gerber‐Lemaire Dr Sami Jannin Prof Geoffrey Bodenhausen |
| Affiliation: | 1. Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne (Switzerland);2. Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115 (USA);3. Department of Chemistry, Indian Institute of Technology, 110 016 New Delhi (India);4. Institut de Chimie Moléculaire de l'Université de Bourgogne (ICMUB), Université de Bourgogne, 21078 Dijon (France);5. Bruker BioSpin AG, Industriestrasse 26, 8117 F?llanden (Switzerland);6. Department of Chemistry, Ecole Normale Supérieure‐PSL Research University, 24 rue Lhomond, 75005 Paris (France);7. Sorbonne Université, UPMC Univ Paris 06, LBM, 4 place Jussieu, 75005 Paris (France);8. CNRS, UMR 7203 LBM, 75005 Paris (France) |
| Abstract: | Transverse and longitudinal relaxation times (T1ρ and T1) have been widely exploited in NMR to probe the binding of ligands and putative drugs to target proteins. We have shown recently that long‐lived states (LLS) can be more sensitive to ligand binding. LLS can be excited if the ligand comprises at least two coupled spins. Herein we broaden the scope of ligand screening by LLS to arbitrary ligands by covalent attachment of a functional group, which comprises a pair of coupled protons that are isolated from neighboring magnetic nuclei. The resulting functionalized ligands have longitudinal relaxation times T1(1H) that are sufficiently long to allow the powerful combination of LLS with dissolution dynamic nuclear polarization (D‐DNP). Hyperpolarized weak “spy ligands” can be displaced by high‐affinity competitors. Hyperpolarized LLS allow one to decrease both protein and ligand concentrations to micromolar levels and to significantly increase sample throughput. |
| Keywords: | drug discovery dynamic nuclear polarization long‐lived states NMR spectroscopy |
