What is a Nuclear Magnetic Resonance Test?

NMR (Nuclear Magnetic Resonance) is an analytical biophysical technique used to study molecular structures by recording how individual nuclei respond to a strong magnetic field. It has the ability to help you directly observe chemical compounds and target biomolecules through ligand-based and protein-based approaches. NMR analysis services are also extremely valuable in hit-to-lead optimization as well as identification of small molecules through fragment screening.

The Advantages of Using NMR Services

  • Non-Destructive and Label-Free: NMR analysis does not require chemical labelling of molecules (like fluorescence tagging) and is non-destructive, allowing for the study of biomolecules in their natural, unmodified state.
  • Detailed Structural Information: Provides detailed information about the 3D structure and dynamics of molecules at the atomic level, crucial for understanding how drugs interact with targets.
  • Solution-State Analysis: Studies molecules in solution, closely mimicking physiological conditions, which is essential for accurately understanding biological processes.

These features make NMR analysis services particularly valuable in drug discovery, for understanding molecular interactions and for studying the dynamics of biological systems. Charles River has an experienced Nuclear Magnetic Resonance testing team that has been providing NMR services to industry and academia for almost 10 years. We have experience not only in ligand-observed and protein-observed methods, but also in studying RNA duplexes and hairpin loops.

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Available NMR Analysis Services

19F Fragment Screening

19F-NMR provides a powerful tool in fragment-based drug discovery. Fluorine’s high gyromagnetic ratio and absence from biological molecules give 19F-NMR high sensitivity and no background, providing clear signals even at very low concentrations. The wide range of chemical shifts and narrow linewidth for the 19F signals of the free ligand allows for high-throughput screening of large mixtures of compounds without the complication of signal overlap.

Charles River's NMR services experts have reviewed the latest trends in fragment library design and applied them to establish a new 500-member 19F labelled library primarily for screening by NMR consisting of fragments from different vendors as well as a subset of fragments synthesized in house and unique to Charles River.

Ligand-observed NMR

This involves monitoring the changes in NMR signal of small molecules (ligands) when they interact with larger target biomolecules like proteins. It is often used as an orthogonal biophysical technique to validate hits from SPR or 19F NMR fragment screening​ as well identifying hits on addition of protein through experiments like:

  • 1H and 19F CPMG (Carr-Purcell-Meiboom-Gill)​
  • 1H STD (Saturation Transfer Difference)
  • WaterLOGSY ​(water Ligand Observed via Gradient SpectroscopY)

This technique requires μg quantities of protein, no labelling, and is protein molecular weight agnostic.​

Protein-observed NMR

This technique lets you directly study the proteins themselves and provides detailed information about the protein’s structure, dynamics, and interactions. It can be used to observe changes in the protein’s structure and dynamics upon binding with a ligand, which is crucial for understanding the mechanism of action of a drug candidate.

Protein-observed NMR can also identify the binding sites of ligands on the protein, helping the design and optimization of drugs that can specifically target and modulate the protein’s activity. A minimum of 15N isotopic labelling is required for protein-observed NMR.

Protein and RNA Assignments

Protein and RNA assignments are used on targets where crystallography has been unsuccessful due to the long time and manpower that it takes to analyze NMR data. However, they provide a wealth of information and are critical in understanding detailed structural and functional studies, such as understanding the binding sites and interaction dynamics between proteins, RNA, and ligands, which is pivotal in drug discovery and understanding biological processes.

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Frequently Asked Questions (FAQs) About NMR Services

  • Which NMR instrument is available to Charles River?

    We have access to a Bruker Avance III 600 MHz spectrometer with a 4-channel, 5-amplifier configuration that includes several NMR probes and a 24-position sample changer.

    In addition to the room-temperature probe, there is the quadruple resonance inverse detection cryoprobe (QCI) for detection of several nuclei to enable the study of a large range of molecules, such as 1H, 2H, 13C, 15N, 31P plus, 19F, and 59Co.

  • What information can NMR services provide?

    NMR services can provide detailed information about molecular structure, dynamic processes, molecular interactions, and chemical environments.

  • What are the limitations of NMR spectroscopy?

    NMR services require relatively high concentrations of sample, is less sensitive compared to some other spectroscopic techniques, and analysis can be complex and time-consuming, especially for large molecules.

  • Does my protein need to be isotopically labelled?

    For ligand-observed experiments, no isotopic labelling is required. However, for protein-observed experiments, isotopic labelling is necessary as it enhances the detection of specific atoms in biomolecules, simplifying and enriching the NMR spectra, particularly for large molecules like proteins.