A Practical Perspective on the Roles of Solution NMR Spectroscopy in Drug Discovery

Abstract

Solution nuclear magnetic resonance (NMR) spectroscopy is a powerful tool to study structures and dynamics of biomolecules under physiological conditions. As there are numerous NMR-derived methods applicable to probe protein–ligand interactions, NMR has been widely utilized in drug discovery, especially in such steps as hit identification and lead optimization. NMR is frequently used to locate ligand-binding sites on a target protein and to determine ligand binding modes. NMR spectroscopy is also a unique tool in fragment-based drug design (FBDD), as it is able to investigate target-ligand interactions with diverse binding affinities. NMR spectroscopy is able to identify fragments that bind weakly to a target, making it valuable for identifying hits targeting undruggable sites. In this review, we summarize the roles of solution NMR spectroscopy in drug discovery. We describe some methods that are used in identifying fragments, understanding the mechanism of action for a ligand, and monitoring the conformational changes of a target induced by ligand binding. A number of studies have proven that 19F-NMR is very powerful in screening fragments and detecting protein conformational changes. In-cell NMR will also play important roles in drug discovery by elucidating protein-ligand interactions in living cells.

Large-Scale Recombinant Production of the SARS-CoV-2 Proteome for High-Throughput and Structural Biology Applications

“…The COVID19-NMR consortium was launched with the motivation of providing NMR assignments of all SCoV2 proteins and RNA elements, and enormous progress has been made since the outbreak of COVID-19 for both components [see Table 2 and ( Wacker et al, 2020 )]. Consequently, we have put our focus on producing proteins in stable isotope-labeled forms for NMR-based applications, e.g., the site-resolved mapping of interactions with compounds ( Li and Kang, 2020 ). Relevant to a broad scientific community, we here report our protocols to suite perfectly any downstream biochemical or biomedical application.…”

Applications of Solution NMR in Drug Discovery

“…Nuclear magnetic resonance (NMR) spectroscopy has been widely used in structure determination and dynamics investigation of biomacromolecules under physiological conditions. Meanwhile, due to its advantages in detecting transient and weak interactions, NMR has been becoming a powerful tool in drug discovery [ 1 , 2 , 3 , 4 ]. FBDD (fragment-based drug discovery), which serves as a key approach for finding high-quality lead candidates, has benefited a lot from NMR spectroscopy development [ 5 , 6 , 7 , 8 , 9 , 10 ].…”

“…Accumulated studies have shown the extensive applications of solution NMR in FBDD field ( Figure 1 ), which include fragment library construction, ligand-observed and target-observed hit screening and validation, etc. [ 2 , 11 ]. During the past decade, FBDD has established itself as a promising drug discovery approach, which has been applied in candidate compound developing for various drug targets such as DNA, RNA, kinases, enzymes, membrane proteins, and even inherently disordered proteins [ 12 , 13 , 14 , 15 ].…”

Using NMR Spectroscopy in the Fragment‐Based Drug Discovery of Small‐Molecule Anticancer Targeted Therapies

“…NMR spectroscopy holds the key advantages of being able to directly identify weakly binding components in a mixture of potential ligands, to discern the binding epitope of a ligand, and to identify binding pockets within a target protein [56,57] . These features make NMR screening particularly well‐suited for FBDD, giving the technique great potential in the rational design of novel targeted therapies [58,59] . It is important to stress that FBDD, including NMR‐based FBDD, does not necessarily constitute a replacement for the well‐established HTS techniques.…”

“…[56,57] These features make NMR screening particularly well-suited for FBDD, giving the technique great potential in the rational design of novel targeted therapies. [58,59] It is important to stress that FBDD, including NMR-based FBDD, does not necessarily constitute a replacement for the wellestablished HTS techniques. Rather, it provides a synergistic approach that focuses on maximizing the binding efficiency of ligands.…”