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Softley, C. ; Bostock, M.J. ; Popowicz, G.M. ; Sattler, M.

Paramagnetic NMR in drug discovery.

J. Biomol. NMR 74, 287–309 (2020)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
The presence of an unpaired electron in paramagnetic molecules generates significant effects in NMR spectra, which can be exploited to provide restraints complementary to those used in standard structure-calculation protocols. NMR already occupies a central position in drug discovery for its use in fragment screening, structural biology and validation of ligand-target interactions. Paramagnetic restraints provide unique opportunities, for example, for more sensitive screening to identify weaker-binding fragments. A key application of paramagnetic NMR in drug discovery, however, is to provide new structural restraints in cases where crystallography proves intractable. This is particularly important at early stages in drug-discovery programs where crystal structures of weakly-binding fragments are difficult to obtain and crystallization artefacts are probable, but structural information about ligand poses is crucial to guide medicinal chemistry. Numerous applications show the value of paramagnetic restraints to filter computational docking poses and to generate interaction models. Paramagnetic relaxation enhancements (PREs) generate a distance-dependent effect, while pseudo-contact shift (PCS) restraints provide both distance and angular information. Here, we review strategies for introducing paramagnetic centers and discuss examples that illustrate the utility of paramagnetic restraints in drug discovery. Combined with standard approaches, such as chemical shift perturbation and NOE-derived distance information, paramagnetic NMR promises a valuable source of information for many challenging drug-discovery programs.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Review
Korrespondenzautor
Schlagwörter Nuclear Magnetic Resonance ; Paramagnetism ; Pseudo-contact Shift ; Paramagnetic Relaxation Enhancement ; Drug Discovery ; Fragment Screening ; Protein-ligand Structure Determination; Nuclear-magnetic-resonance; Lanthanide-binding Tags; Protein-structure Determination; Residual Dipolar Couplings; Model-free Approach; Pseudocontact Shifts; Spin-label; Ligand-binding; Relaxation Enhancements; Structural-analysis
ISSN (print) / ISBN 0925-2738
e-ISSN 1573-5001
Zeitschrift Journal of Biomolecular NMR
Quellenangaben Band: 74, Heft: , Seiten: 287–309 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Van Godewijckstraat 30, 3311 Gz Dordrecht, Netherlands
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)