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Molecules 2017, 22(9), 1492;

Forbidden Coherence Transfer of 19F Nuclei to Quantitatively Measure the Dynamics of a CF3-Containing Ligand in Receptor-Bound States

Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), 2-3-26 Aomi, Koto-ku, Tokyo 135-0064, Japan
Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Author to whom correspondence should be addressed.
Received: 10 August 2017 / Revised: 4 September 2017 / Accepted: 4 September 2017 / Published: 7 September 2017
(This article belongs to the Special Issue Recent Advances in Biomolecular NMR Spectroscopy)
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The dynamic property of a ligand in the receptor-bound state is an important metric to characterize the interactions in the ligand–receptor interface, and the development of an experimental strategy to quantify the amplitude of motions in the bound state is of importance to introduce the dynamic aspect into structure-guided drug development (SGDD). Fluorine modifications are frequently introduced at the hit-to-lead optimization stage to enhance the binding potency and other characteristics of a ligand. However, the effects of fluorine modifications are generally difficult to predict, owing to the pleiotropic nature of the interactions. In this study, we report an NMR-based approach to experimentally evaluate the local dynamics of trifluoromethyl (CF3)-containing ligands in the receptor-bound states. For this purpose, the forbidden coherence transfer (FCT) analysis, which has been used to study the dynamics of methyl moieties in proteins, was extended to the 19F nuclei of CF3-containing ligands. By applying this CF3–FCT analysis to a model interaction system consisting of a ligand, AST-487, and a receptor, p38α, we successfully quantified the amplitude of the CF3 dynamics in the p38α-bound state. The strategy would bring the CF3-containing ligands within the scope of dynamic SGDD to improve the affinity and specificity for the drug-target receptors. View Full-Text
Keywords: NMR spectroscopy; dynamics; structural biology; drug development; trifluoromethyl NMR spectroscopy; dynamics; structural biology; drug development; trifluoromethyl

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Tokunaga, Y.; Takeuchi, K.; Shimada, I. Forbidden Coherence Transfer of 19F Nuclei to Quantitatively Measure the Dynamics of a CF3-Containing Ligand in Receptor-Bound States. Molecules 2017, 22, 1492.

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