Paramagnetic NMR in drug discovery

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.

Paramagnetic NMR Spectroscopy Is a Tool to Address Reactivity, Structure, and Protein–Protein Interactions of Metalloproteins: The Case of Iron–Sulfur Proteins

“…However, probably the most intriguing aspect is the use of metal-based spin labels as an additional source of structural constraints in diamagnetic proteins. This succeeded to extend the range of systems that can be studied via paramagnetic NMR: extrinsic paramagnetic centers contributed to promote the applications of paramagnetic NMR also beyond structural biology in solution [19][20][21][22][23][24][25].…”

NMR as a “Gold Standard” Method in Drug Design and Discovery

“…Paramagnetic NMR (PNMR) can also play a prominent role in drug discovery [ 341 ], as PNMR can provide key structural information in situations where crystal structures cannot due to the weak binding of ligands [ 341 ]. PNMR can be used to quantify the binding between ligands and large biomolecules such as proteins, DNA, and RNA [ 342 ].…”

“…PNMR depends on the presence of a group (called the paramagnetic center) with an unpaired electron [ 343 ], and since many naturally occurring biomolecules and organic compounds lack a paramagnetic center, one such as caged lanthanide (CLaNP) [ 344 ], must be introduced artificially [ 341 ]. Once the paramagnetic center (often a metal ion) is present, paramagnetic effects can be used to measure the distance and the relative orientation (i.e., angle) between molecules [ 345 ].…”

“…Thus, PNMR is quite a useful technique for drug discovery when a paramagnetic center is present. The most relevant consequence of PNMR for drug discovery is paramagnetic relaxation enhancement (PRE), although there are a number of studies demonstrating the use of pseudocontact shift (PCS) effect in drug discovery research [ 341 ].…”

“…Paramagnetic relaxation enhancement (PRE) is proportional to the inverse sixth power of the distance between the paramagnetic center and the nucleus of interest (i.e., 1 H), although it does not reveal anything about relative orientation [ 341 ]. PRE can give quantitative information in the range of 10–25 Angstroms [ 346 ].…”