Cross-Correlated 19F Relaxation Measurements for the Study of Fluorinated Ligand–Receptor Interactions

Peng, Jeffrey W.

doi:10.1006/jmre.2001.2422

Cited by 35 publications

(21 citation statements)

References 40 publications

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“…13 C-labeling of the reporter ligand at one position [65] or more sophisticated NMR experiments [64] are a possible remedy. A promising approach is the use of 19 F-spectroscopy, which is a nucleus very suitable for NMR screening [7,44,46,68]. Combination with competition experiments is a very elegant method to circumvent sig- significant chemical shift changes and broader lines of these compounds in the presence of target protein.…”

Section: Hit Validation By Nmrmentioning

confidence: 99%

Protein NMR in biomedical research

Jahnke

Widmer

2004

CMLS, Cell. Mol. Life Sci.

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Nuclear magnetic resonance (NMR) spectroscopy is a versatile biophysical technique with wide applicability in drug discovery research, particularly for the detection and characterization of molecular interactions. This review highlights in a comprehensive manner the aspects of biomolecular NMR which are most beneficial for pharmaceutical research and presents them as contributions to the different stages of a drug discovery program: target selection, assay development, lead generation and lead optimization. Emphasis is put on the concept of the particular NMR application, rather than on technical details, and on recent examples. Finally, an appendix of frequently asked questions is given.

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Section: Hit Validation By Nmrmentioning

confidence: 99%

Protein NMR in biomedical research

Jahnke

Widmer

2004

CMLS, Cell. Mol. Life Sci.

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“…fluorinated compounds to a target. 3,56 The properties of fluorine that make it useful for protein target detected screening apply to ligand-detected methods as well. Most notably, the extraordinary sensitivity of 19 F to its environment and local shielding effects means that its resonances are dispersed over a large chemical shift range and it is extremely sensitive to relaxation changes caused by binding, which can provide more resolution than 1 H NMR relaxation experiments.…”

Section: Relaxation Experimentsmentioning

confidence: 99%

High-field solution NMR spectroscopy as a tool for assessing protein interactions with small molecule ligands

Skinner

Laurence

2008

Journal of Pharmaceutical Sciences

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The ability of a small molecule to bind and modify the activity of a protein target at a specific site greatly impacts the success of drugs in the pharmaceutical industry. One of the most important tools for evaluating these interactions has been high-field solution NMR because of its unique ability to examine even weak protein-drug interactions at high resolution. NMR can be used to evaluate the structural, thermodynamic and kinetic aspects of a binding reaction. The basis of NMR screening experiments is that binding causes a perturbation in the physical properties of both molecules. Unique properties of small and macromolecules allow selective detection of either the protein target or ligand, even in a mixture of compounds. This review outlines current methodologies for assessing protein-ligand interactions from the perspectives of the protein target and ligand and delineates the fundamental principles for understanding NMR approaches in drug research. Advances in instrumentation, pulse sequences, isotopic labeling strategies, and the development of competition experiments support the study of higher molecular weight protein targets, facilitate higher-throughput and expand the range of binding affinities that can be evaluated, enhancing the utility of NMR for identifying and characterizing potential therapeutics to druggable protein targets.

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“…Keywords: fluorine · imaging agents · lanthanides · magnetic properties · NMR spectroscopy search into fluorinated materials suitable for detection in vivo. [8,9] The published works range from quantitative NMR spectroscopic tracking of the metabolism of fluorinated drugs [10] to imaging studies of organ inflammation processes by using chemically inert perfluorinated compounds as contrast agents. [11] Perfluorocarbons have also been used to signal changes in local oxygen pressure as a consequence of their interaction with this paramagnetic species in vivo.…”

Section: Introductionmentioning

confidence: 99%

Design Principles and Theory of Paramagnetic Fluorine‐Labelled Lanthanide Complexes as Probes for ¹⁹F Magnetic Resonance: A Proof‐of‐Concept Study

Chalmers

Luca

Hogg

et al. 2009

Chemistry A European J

143

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The synthesis and spectroscopic properties of a series of CF(3)-labelled lanthanide(III) complexes (Ln=Gd, Tb, Dy, Ho, Er, Tm) with amide-substituted ligands based on 1,4,7,10-tetraazacyclododecane are described. The theoretical contributions of the (19)F magnetic relaxation processes in these systems are critically assessed and selected volumetric plots are presented. These plots allow an accurate estimation of the increase in the rates of longitudinal and transverse relaxation as a function of the distance between the Ln(III) ion and the fluorine nucleus, the applied magnetic field, and the re-rotational correlation time of the complex, for a given Ln(III) ion. Selected complexes exhibit pH-dependent chemical shift behaviour, and a pK(a) of 7.0 was determined in one example based on the holmium complex of an ortho-cyano DO3A-monoamide ligand, which allowed the pH to be assessed by measuring the difference in chemical shift (varying by over 14 ppm) between two (19)F resonances. Relaxation analyses of variable-temperature and variable-field (19)F, (17)O and (1)H NMR spectroscopy experiments are reported, aided by identification of salient low-energy conformers by using density functional theory. The study of fluorine relaxation rates, over a field range of 4.7 to 16.5 T allowed precise computation of the distance between the Ln(III) ion and the CF(3) reporter group by using global fitting methods. The sensitivity benefits of using such paramagnetic fluorinated probes in (19)F NMR spectroscopic studies are quantified in preliminary spectroscopic and imaging experiments with respect to a diamagnetic yttrium(III) analogue.

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Cross-Correlated 19F Relaxation Measurements for the Study of Fluorinated Ligand–Receptor Interactions

Cited by 35 publications

References 40 publications

Protein NMR in biomedical research

Protein NMR in biomedical research

High-field solution NMR spectroscopy as a tool for assessing protein interactions with small molecule ligands

Design Principles and Theory of Paramagnetic Fluorine‐Labelled Lanthanide Complexes as Probes for ¹⁹F Magnetic Resonance: A Proof‐of‐Concept Study

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Cross-Correlated 19F Relaxation Measurements for the Study of Fluorinated Ligand–Receptor Interactions

Cited by 35 publications

References 40 publications

Protein NMR in biomedical research

Protein NMR in biomedical research

High-field solution NMR spectroscopy as a tool for assessing protein interactions with small molecule ligands

Design Principles and Theory of Paramagnetic Fluorine‐Labelled Lanthanide Complexes as Probes for 19F Magnetic Resonance: A Proof‐of‐Concept Study

Contact Info

Product

Resources

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Design Principles and Theory of Paramagnetic Fluorine‐Labelled Lanthanide Complexes as Probes for ¹⁹F Magnetic Resonance: A Proof‐of‐Concept Study