NMR Spectroscopy Revolutionizes Drug Discovery

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A recent study from the Journal of Medicinal Chemistry examined how nuclear magnetic resonance (NMR) spectroscopy is being used in drug discovery.

Nuclear magnetic resonance (NMR) spectroscopy is poised to drive advancements in drug discovery now and in the future, according to a recent article published in the Journal of Medicinal Chemistry (1).

Thanks to the advent of drug design and manufacturing technology, the drug discovery landscape has been constantly changing, particularly over the past decade or so. It was during this time that NMR spectroscopy began to be used in this space regularly. Historically, NMR has been a cornerstone for elucidating the structure of small molecules (1). However, recent innovations have broadened its scope to use NMR in structure-based drug discovery (SBDD) (2). One of the main reasons for using NMR is because of the technique’s ability to target biomolecules and observe chemical compounds directly (2). This powerful analytical tool has expanded its applications beyond traditional medicinal chemistry, becoming instrumental in characterizing a wide array of small molecules and novel drug modalities as a result (1).

Modern medical research laboratory two scientists working, Analyzing test, Advanced scientific pharmaceutical lab for medicine biotechnology. Generated with AI | Image Credit: © 361 Portrait Studio - stock.adobe.com

Modern medical research laboratory two scientists working, Analyzing test, Advanced scientific pharmaceutical lab for medicine biotechnology. Generated with AI | Image Credit: © 361 Portrait Studio - stock.adobe.com

NMR works by exploiting the magnetic properties of certain atomic nuclei, such as hydrogen-1 or carbon-13 that absorb and re-emit electromagnetic radiation at characteristic frequencies when placed in a strong magnetic field. By measuring these frequencies, NMR provides detailed information about the electronic environment surrounding these nuclei, which in turn reveals the number and types of atoms in a molecule, their connectivity, and even their spatial arrangement. This information is obtained from various NMR parameters such as chemical shifts, coupling constants, and signal intensities, allowing scientists to construct a detailed picture of the molecule's structure and molecular environment.

A recent article published by lead author Janet Caceres-Cortes and her team at Bristol-Myers Squibb highlights the significant advancements and future potential of NMR-derived methods in drug discovery. Their published paper emphasizes the versatility of NMR spectroscopy in the drug development process.

Caceres-Cortes and her colleagues highlighted several key advancements in NMR technology that have enhanced its utility in drug discovery. One notable development the team discusses is the use of high-field NMR spectrometers, which have provided unprecedented resolution and sensitivity (1). Using these instruments have allowed for the detailed analysis of large biomolecules and their interactions with potential drug candidates, facilitating a deeper understanding of their mechanisms of action (1). Additionally, the integration of cryoprobes and advanced pulse sequences has significantly improved the efficiency and accuracy of NMR measurements, enabling researchers to obtain high-quality data in less time.

The application of NMR in lead optimization was also addressed in this study. The research team highlighted how NMR-based fragment screening has emerged as a powerful strategy for identifying small molecules that bind to target proteins (1). This approach involves screening a library of low-molecular-weight compounds to identify those that interact with the protein of interest (1). The hits identified through this method can then be optimized into potent and selective drug candidates. NMR's ability to provide detailed information on the binding interactions at the atomic level makes it an ideal tool for this purpose (1).

The research team also discussed the role of paramagnetic NMR spectroscopy to study protein–ligand interactions. This technique leverages the paramagnetic properties of certain metal ions to enhance the NMR signals of nearby nuclei, providing valuable insights into the spatial arrangement of atoms within the complex (1). Another exciting development is the combination of NMR with other biophysical methods, such as cryo-electron microscopy and X-ray crystallography, to obtain complementary information that can guide the design of novel therapeutic agents (1).

The perspective concludes with a forward-looking view on the future of NMR in drug discovery. Because of advances in experimental protocols, instrumentation, and computational methods, NMR spectroscopy is poised to continue to be used in this space to help develop therapeutic agents (1). The insights gained from NMR studies will not only enhance our understanding of biological processes but also pave the way for the next generation of medicines (1).

The advancements in NMR-derived methods have expanded its applications beyond traditional boundaries, making it an essential tool in the pursuit of innovative therapeutic agents.


(1) Caceres-Cortes, J.; Falk, B.; Mueller, L.; Dhar, T. G. M. Perspectives on Nuclear Magnetic Resonance Spectroscopy in Drug Discovery Research. J. Med. Chem. 2024, 67 (3), 1701–1733. DOI: 10.1021/acs.jmedchem.3c02389

(2) Sugiki, T.; Furuita, K.; Fujiwara, T.; Kojima, C. Current NMR Techniques for Structure-Based Drug Discovery. Molecules 2018, 23 (1), 148. DOI: 10.3390/molecules23010148

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