Chemmedchem 2014-11-01

Drug screening boosted by hyperpolarized long-lived states in NMR.

Roberto Buratto, Aurélien Bornet, Jonas Milani, Daniele Mammoli, Basile Vuichoud, Nicola Salvi, Maninder Singh, Aurélien Laguerre, Solène Passemard, Sandrine Gerber-Lemaire, Sami Jannin, Geoffrey Bodenhausen

文献索引：ChemMedChem 9(11) , 2509-15, (2014)

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摘要

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((1)H) 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.© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.