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 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.
Highlights
NMR spectroscopy is well established as a core technique in drug discovery for ligand and fragment screening, validation of target interactions and, in cases where it is not possible to obtain crystal structures of protein–ligand complexes, for structure determination (Hajduk et al 1999; Gossert and Jahnke 2016; Erlanson et al 2016)
NMR spectroscopy is uniquely sensitive to the presence of a paramagnetic center since the strength of magnetic interactions between nuclear and electron spins depends on the involved gyromagnetic ratios, which is about 658 times stronger for an unpaired electron compared to a proton nuclear spin
In solution NMR, paramagnetic effects are mostly exploited through three main phenomena: paramagnetic relaxation enhancement (PRE), pseudo-contact shifts (PCS) and residual dipolar couplings (RDC), additional mechanisms have been used to study the structure and dynamics of proteins
Summary
NMR spectroscopy is well established as a core technique in drug discovery for ligand and fragment screening, validation of target interactions and, in cases where it is not possible to obtain crystal structures of protein–ligand complexes, for structure determination (Hajduk et al 1999; Gossert and Jahnke 2016; Erlanson et al 2016). In solution NMR, paramagnetic effects are mostly exploited through three main phenomena: paramagnetic relaxation enhancement (PRE), pseudo-contact shifts (PCS) and residual dipolar couplings (RDC), additional mechanisms have been used to study the structure and dynamics of proteins. In addition to paramagnetic relaxation due to the Solomon mechanism ( Rp2,aSraB ), the presence of an external magnetic field leads to differing populations of the S and I spin energy levels according to the Boltzmann distribution (splitting is given by MS and MI respectively) (Bertini et al 2002a, b).
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