Paramagnetic NMR in drug discovery.

Journal of Biomolecular NMR
Charlotte A SoftleyMichael Sattler

Abstract

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...Continue Reading

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Citations

Sep 5, 2020·Journal of Biomolecular NMR·Raymond S Norton, Wolfgang Jahnke
Jul 28, 2020·Journal of Biomolecular NMR·Michele InverniciMario Piccioli
Oct 31, 2020·The FEBS Journal·Inês B TrindadeMario Piccioli
Jan 28, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Li Shi, Naixia Zhang
Oct 15, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Abdul-Hamid EmwasMariusz Jaremko
Apr 22, 2021·Current Opinion in Chemical Biology·Fabio Arnesano
Aug 30, 2021·Toxicon : Official Journal of the International Society on Toxinology·Karoline SanchesRaymond S Norton
Jan 28, 2022·Chemical Reviews·Qing MiaoMarcellus Ubbink

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Methods Mentioned

BETA
NMR
X-ray
chemical shift
exchange
chemical exchange saturation transfer

Software Mentioned

Echidna
AutoDock Vina HADDOCK
NIH
WaterLOGSY
SLAPSTIC
Xplor
HADDOCK
AutoDock

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