期刊
CHEMMEDCHEM
卷 9, 期 11, 页码 2509-2515出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201402214
关键词
drug discovery; dynamic nuclear polarization; long-lived states; NMR spectroscopy
资金
- Swiss National Science Foundation (SNSF)
- Swiss Commission for Technology and Innovation (CTI)
- Ecole Polytechnique Federale de Lausanne (EPFL), Switzerland
- French National Centre for Scientific Research (CNRS)
- European Research Council (ERC)
Transverse and longitudinal relaxation times (T-1 and T-1) 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 T-1(H-1) 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.
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