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

Abstract

Against the challenge of providing personalized cancer care, the development of targeted therapies stands as a promising approach. The discovery of these agents can benefit from fragment‐based drug discovery (FBDD) methods that help guide ligand design and provide key structural information on the targets of interest. In particular, nuclear magnetic resonance spectroscopy is a promising biophysical tool in fragment discovery due to its detection capabilities and versatility. This review provides an overview of FBDD, describes the basis of NMR‐based fragment screening, summarizes some exciting technical advances reported over the past decades, and closes with a discussion of selected case studies where this technique has been used as part of drug discovery campaigns to produce lead compounds towards the design of anti‐cancer targeted therapies.

Perspectives on Nuclear Magnetic Resonance Spectroscopy in Drug Discovery Research

“…NMR, STD, and HSQC experiments identify binding to KRAS with subsequent structure-based design. Adapted with permission from ref . Copyright 2023 John Wiley and Sons.…”

“…Fragment library screening by NMR was utilized in the continued efforts to probe additional binding pockets, including the switch I/II pocket of KRAS, leading to the discovery of nanomolar inhibitors. , An 1800-fragment library was screened against the KRAS SI/II pocket using STD NMR, 1 H– 15 N HSQC NMR and microscale thermophoresis (MST) revealing 55 fragment hits which featured indole moieties that were optimized to maximize polar interactions in the binding site (Figure ). X-ray crystallography and ligand-based SAR yielded nanomolar-affinity compound, 1 which was shown to inhibit GDP–GTP exchange, prevent important protein–KRAS interactions, and affect downstream signaling and cancer cell survival.…”

Screening strategies for identifying RNA- and ribonucleoprotein-targeted compounds

“…Finally, natural compounds used in RNA screens because of their intrinsic chemical diversity are difficult to detect by MS. A useful complement to MS screens is offered by fragment-based affinity screens, which use molecules with minimal chemical complexity unlikely to display high-affinity binding but with strong potential for optimization by the combination of different fragments (Example 7; Figure 2). NMR is particularly well suited for fragment-based screens despite its lower throughput because it can detect hits with millimolar K D and visualize their binding at high resolution, which is useful in hit optimization [40,41]. When relying on NMR, fragment-based screens are particularly useful against small (<30 kDa), highly structured RNAs (Example 9).…”

19F chemical library and 19F-NMR for a weakly bound complex structure

“…NMR spectroscopy is useful for analyzing high-concentration solutions and detecting weak interactions and is thus frequently used in FBDD for screening and hit validation. 3,4…”