Editorial Feature

The Role of Nuclear Magnetic Resonance Spectroscopy in Drug Discovery

Advanced techniques for rapid drug development are becoming increasingly essential as pathogens continuously evolve and genetic alterations in cancer cells accumulate.  However, the underlying mechanisms and pathology of many neurological diseases remain unknown. Going forward, a necessary focus is the molecular study of diseases to facilitate the development of efficient drug discovery techniques.1

The Role of Nuclear Magnetic Resonance Spectroscopy in Drug Discovery

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Modern drug discovery technologies are time consuming and expensive, with new drugs taking more than ten years to commercialize and costing over a billion U.S. dollars to develop.

Nuclear magnetic resonance (NMR) spectroscopy has emerged as an alternative technique, exhibiting the potential to become a “gold standard” platform for pharmaceutical design and discovery.1

This article explores the application and advantages of NMR in drug development.

Introduction to NMR

NMR spectroscopy is based on the detection of individual nuclei spins, which vary according to atomic, electronic, and chemical conditions. The specimen under study is positioned in a static, strong, uniform magnetic field, around which the nuclear spins exhibit Larmor precessions.

Subsequently, a radiofrequency electromagnetic field is applied perpendicular to the static magnetic field plane. The resulting magnetization induces a measurable oscillating voltage in the NMR receiver coil that is modified using a Fourier Transform model to represent the sample’s molecular structure with atomic resolution.1

NMR spectroscopy is a versatile method used to study biomolecules and perform biophysical analysis of drugs. It provides details about molecular binding, interactions, and conformations. The NMR spectra of drugs and their targets reveal atomic-level interactions between them. As a non-destructive technique, NMR spectroscopy also facilitates repeated sample analysis.1

NMR is, therefore, an indispensable tool in pharmaceutical research, playing a crucial role in the structural characterization and quantitation of drug substances, reaction monitoring during chemical synthesis, impurity detection, and solid-state characterization of the final drug.2

Applications of NMR in Drug Discovery

NMR plays multiple roles in target-based drug discovery. The most common drug screening technique—fragment-based drug design—employs NMR in different ways. Target-based screening uses NMR to construct the structure-activity-relationship (SAR), enabling the discovery and development of strongly binding ligands. Ligand-based screening uses NMR to locate the target binding site.1

NMR is also used to identify and optimize lead compounds, as it can determine the location and the chemical shift information of elements commonly present in drug substances, including hydrogen, carbon, nitrogen, and fluorine. This structural elucidation accelerates the drug discovery process and aids in scaling up production.2

Small-molecule drug substances form the base of a drug. They are typically isolated from natural sources or organically synthesized. During synthesis, the characterization of all the materials involved (starting materials, intermediates, and drug substances) is essential to identify targets, improve efficacy, and minimize the adverse effects of a drug.

In addition to the detailed characterization of small molecules, NMR methods can be applied to study the relative arrangement of drug substances with more than two stereocenters.2

It is important to note that not all drugs are small molecules. Biomacromolecules, including therapeutics such as antibodies and other proteins, also occupy a large share of the drug market. For this critical category of drugs, NMR is applied for quality control, ensuring batch-to-batch consistency, optimal properties, and stability.3

During drug formulation, NMR is applicable in both liquid and solid states. Liquid-state NMR is primarily used to study the structure of impurities separated from drug products during stability studies and to detect related toxicity or genotoxicity.

Alternatively, solid-state NMR reveals drug configurations, any degradation due to interactions with the excipients, and quantitation of the formulated solid-form drugs. Quantitation by NMR (qNMR) can ascertain the purity of different constituents and reaction yields.2

The drug development process involves multi-step reactions that require high levels of control and can exhibit low yields. Reaction monitoring by NMR allows kinetic analysis and a comprehensive understanding of reaction mechanisms.

This understanding could facilitate the use of one-pot reactions in the future, providing better control and higher yields, improving the efficiency of drug synthesis..2 Inhibitors or enhancers of enzyme reactions can also be identified through NMR screening.3

Analyzing the arrangement of regioisomers is essential to drug synthesis, as variations in regioisomerism can alter the mode of action, function, and side effects of molecules. NMR can uniquely identify the correct regioisomer, providing an advantage over other analytical methods like mass spectrometry, which only considers the molar mass of molecules rather than their distinct chemical arrangement. .2 

Enhancing Drug Design Through NMR

The utilization of NMR in improving drug efficacy against difficult and complex targets is well established. A recent study in the Journal of Medicinal Chemistry demonstrated how NMR is used to establish robust SARs for efficient drug design by obtaining accurate binding and affinity measurements. These SARs help expedite hit-to-lead discovery and mitigate false positives and negatives, as well as common hit validation errors.

The researchers highlighted the efficacy of the proposed method by generating excellent micromolar binders from the primary millimolar fragment screening hits against an “undruggable” cancer-related protein target.4

Another recent study in Expert Opinion on Drug Discovery proposed the use of NMR-based drug discovery to target protein misfolding and aggregation, which is responsible for over 50 human disorders, including Alzheimer’s and Parkinson’s diseases.

NMR can help identify small molecules, such as fasudil, capable of binding disordered proteins and inhibiting their aggregation. The systematic optimization of compound potency and drug-target interactions using the structural and dynamic insights provided by NMR can result in the identification of small molecules with better target engagement.5

Future Outlooks and Advancements

NMR spectroscopy exhibits growing synergy with emerging technologies like deep learning and artificial intelligence (AI). Biomolecular NMR spectroscopy can be combined with AI-based structural predictions to address existing knowledge gaps and assist in the accurate characterization of protein dynamics, allostery, and conformational heterogeneity.6

AI-based tools can also advance the acquisition and analysis of NMR spectra, improving their accuracy and reliability,  thus simplifying pharmaceutical experiments.

The AI-NMR combination has the potential to revolutionize structural biology in multiple ways, enhance our knowledge of complex biomolecular systems, and fast-track drug discovery processes.6

Overall, NMR spectroscopy has a unique role in drug design and discovery. Ultra-high magnetic field NMR spectrometers are being developed to enhance its sensitivity and resolution.1 In the future, NMR's speed, simplicity, and reproducibility will significantly enhance the efficiency of pharmaceutical development.

More from AZoOptics: Attosecond Spectroscopy: Advancements in Ultrafast Molecular Dynamics

References and Further Reading

1. Emwas, A.-H., Szczepski, K., Poulson, BG., Chandra, K., McKay, RT., Dhahri, M., Alahmari, F., Jaremko, L., Lachowicz, JI., Jaremko, M. (2020). NMR as a “Gold Standard” Method in Drug Design and Discovery. Molecules. doi.org/10.3390/molecules25204597

2. Mantle, MD., Hughes, LP. (2024). Magnetic Resonance and Its Applications in Drug Formulation and Delivery. Royal Society of Chemistry. doi.org/10.1039/9781788019996-00001

3. Norton, RS., Jahnke, W. (2020). NMR in pharmaceutical discovery and development. Journal of Biomolecular NMR. doi.org/10.1007/s10858-020-00345-7

4. Larda, ST., Ayotte, Y., Denk, MM., Coote, P., Heffron, G., Bendahan, D., Shahout, F., Girard, N., Iddir, M., Bouchard, P., Bilodeau, F., Woo, S., Farmer, LJ., LaPlante, SR. (2023). Robust Strategy for Hit-to-Lead Discovery: NMR for SAR. Journal of Medicinal Chemistry. doi.org/10.1021/acs.jmedchem.3c00656v

5. Vendruscolo, M. (2023). Thermodynamic and kinetic approaches for drug discovery to target protein misfolding and aggregation. Expert Opinion on Drug Discovery. doi.org/10.1080/17460441.2023.2221024

6. Shukla, VK., Heller, GT., Hansen, DF. (2023). Biomolecular NMR spectroscopy in the era of artificial intelligence. Structure. doi.org/10.1016/j.str.2023.09.011

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Nidhi Dhull

Written by

Nidhi Dhull

Nidhi Dhull is a freelance scientific writer, editor, and reviewer with a PhD in Physics. Nidhi has an extensive research experience in material sciences. Her research has been mainly focused on biosensing applications of thin films. During her Ph.D., she developed a noninvasive immunosensor for cortisol hormone and a paper-based biosensor for E. coli bacteria. Her works have been published in reputed journals of publishers like Elsevier and Taylor & Francis. She has also made a significant contribution to some pending patents.  


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