Solution NMR Spectroscopy in Target-Based Drug Discovery

Abstract

Solution NMR spectroscopy is a powerful tool to study protein structures and dynamics under physiological conditions. This technique is particularly useful in target-based drug discovery projects as it provides protein-ligand binding information in solution. Accumulated studies have shown that NMR will play more and more important roles in multiple steps of the drug discovery process. In a fragment-based drug discovery process, ligand-observed and protein-observed NMR spectroscopy can be applied to screen fragments with low binding affinities. The screened fragments can be further optimized into drug-like molecules. In combination with other biophysical techniques, NMR will guide structure-based drug discovery. In this review, we describe the possible roles of NMR spectroscopy in drug discovery. We also illustrate the challenges encountered in the drug discovery process. We include several examples demonstrating the roles of NMR in target-based drug discoveries such as hit identification, ranking ligand binding affinities, and mapping the ligand binding site. We also speculate the possible roles of NMR in target engagement based on recent processes in in-cell NMR spectroscopy.

An Engineered Microvirin Variant with Identical Structural Domains Potently Inhibits Human Immunodeficiency Virus and Hepatitis C Virus Cellular Entry

“…On the other hand, in the case of LUMS1, chemical shift perturbation in most of the cross-peaks were in the form of line broadening suggesting intermediate exchange on the NMR time scale. Slow exchange on the NMR time scale is related to higher binding affinity (lower K D values) as compared to intermediate exchange [31]. The two lectins, therefore, demonstrate the difference in binding to carbohydrate in terms of affinity.…”

Application of Fragment-Based Drug Discovery to Versatile Targets

“…Compared with other methods, NMR screening gives rise to less false positive hits and a mixture of fragments can be screened. A number of NMR experiments have been utilized in FBDD by identifying various hits binding to a specific site on targets ( Gossert and Jahnke, 2016 ; Norton et al, 2016 ; Li and Kang, 2017 ; Sugiki et al, 2018 ; Kang, 2019a , b ). As shown in Table 1 , several methods can be applied in fragment screening.…”

“…Screening can be carried out to monitor release of the spy molecule, which is able to identify the required fragments. 19 F-based NMR is very useful for achieving this goal (Li and Kang, 2017;Kang, 2019b). 1 H-15 N-HSQC based screening plays important roles in screening fragments binding to different sites.…”

Systematic in silico Evaluation of Leishmania spp. Proteomes for Drug Discovery

“…In phenotypic screening it is possible to select compounds with cytotoxicity against the whole cell, measure cellular function without imposing the need for prior knowledge about the targets; While in target-based approaches the process of developing a new drug has as its key point the discovery of a target or a set of targets (Gilbert, 2013 ; Schenone et al, 2013 ; Swinney, 2013 ). This knowledge about the target, different from what occurs in the phenotypic screening method, allows access to crucial information for the optimization of compounds, such as knowledge about the target/drug binding site (Gilbert, 2013 ; Li and Kang, 2017 ). However, target selection is often based on biological evidence which results in the analysis of a small target group, exploring only a small portion of the total proteome and neglecting potentially therapeutically important new drug targets (Patel et al, 2013 ; Schenone et al, 2013 ).…”