NMR spectrometry analysis for drug discovery and development
In drug development and discovery, NMR spectrometry plays a central role in the analysis of molecular structures. NMR screening methods provide a valuable and reliable tool for hit-to-lead optimization and identification of small molecules.
Usually a library of compounds is checked for “hits” (such as particular ligands) that may bind to a specific target. The results can then be validated and advanced for potential future development using NMR binding assays. However, this application is generally limited to higher field NMR instruments.
Benchtop NMR excels in the later stages of the drug development and manufacturing process, where precision identification of small molecules continues to be a critical factor. The requirements of an approved “reference standard” must be met by all pharmaceutical products. It is common for NMR to provide the information necessary to create these standards and is also applied during manufacturing to ensure that intermediates and final products consistently meet them.
In many cases, a simple one-dimensional hydrogen spectrum can quickly verify a structure based on peak splitting, chemical shift, and integral value. For simple small molecules, much of this analysis can be automated using standard routines.
If the molecule is more complex, some signals in the one-dimensional spectrum may overlap. A powerful benchtop NMR spectrometer, such as the X Pulsecan provide a variety of one-dimensional and two-dimensional experiments to enable structural confirmation and even whole-molecule structural elucidation for unknowns.
Structure of the drug gemfibrozil
Figure 1 illustrates the chemical composition of the drug gemfibrozil, also known by its IUPAC name 5-(2,5-dimethylphenoxy)-2,2-dimethyl-pentanoic acid and its empirical formula C15H22O3. As a member of the fibrate class of molecules, it regulates blood lipids by reducing triglyceride and LDL cholesterol levels while increasing HDL levels, thereby reducing the risk of heart disease.
Figure 1. 1D and 2D NMR spectra of gemfibrozil. Image Credit: Oxford Instruments NMR
Figure 1 illustrates the fully decoupled carbon spectrum (left), the one-dimensional hydrogen spectrum (top), and the two-dimensional spectrum 1H–13C HSQC spectrum. In the HSQC spectrum, plotted as a contour map, peaks can be observed at the chemical shift coordinates corresponding to the shift of a hydrogen nucleus and the relative carbon nucleus to which it is bonded. The arrows in the diagram illustrate these examples.
A 1H-13The C HMBC spectrum can be used to assign longer range bonding correlations between hydrogen and carbon nuclei within the molecule. By blending the data obtained from these spectra, the characteristic peaks of the molecule can be clearly identified and the molecular structure of the active end product can be confirmed.
Download the application note to learn more about confirming and understanding your candidate molecules or reaction intermediates with benchtop NMR
Oxford Instruments NMR offers a range of Nuclear Magnetic Resonance (NMR) instruments to multiple industries.
Our NMR portfolio includes X-Pulse, a 60 MHz, high-resolution, cryogen-free benchtop NMR spectrometer that provides high-quality 1- and 2-D NMR spectra of 1H, 19F, 13C, and 31P. The MQC+ line of benchtop NMR analyzers has many applications in the agriculture, food, consumer products, textile and polymer industries.
MQC+ analyzers are used to measure oil, water, fluorine and solid fats in a variety of samples and are typically used for quality assurance and quality control. Our GeoSpec NMR core analyzers are designed specifically for the study of core samples from oilfield reservoirs, with installations in nearly every major oil producer and SCAL laboratory worldwide.