In drug development and discovery, NMR spectrometry plays a pivotal role in the analysis of molecular structures. NMR screening methods provide a valuable and reliable tool for hit-to-lead optimization and the identification of small molecules.
Usually, a compound library is checked for “hits” (such as particular ligands) that can bind to a specific target. The hits can then be validated and advanced for potential future development using NMR binding tests. However, this application is typically limited to higher field NMR instruments.
Benchtop NMR excels in the later stages of the drug development and manufacturing process, where the accurate identification of small molecules continues to be a critical factor. The requirements of an approved “reference standard” must be met by all drug products. It is common for NMR to provide the information necessary to create these standards and also be applied in-process to make sure that the intermediates and end products consistently meet them.
In several cases, a simple one-dimensional hydrogen spectrum can quickly verify a structure based on the peak splitting, chemical shift, and integral value. For simple small molecules, a significant portion 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 high-performance benchtop NMR spectrometer, like the X-Pulse, can provide a variety of one-dimensional and two-dimensional experiments to allow 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 raising HDL levels, thereby reducing the risk of heart disease.
Figure 1. Gemfibrozil 1D and 2D NMR spectra. Image Credit: Oxford Instruments
Figure 1 depicts the fully decoupled carbon spectrum (left), the one-dimensional hydrogen spectrum (top), and the two-dimensional 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-13C HMBC spectrum can be employed to assign longer-range through-bond correlations between hydrogen and carbon nuclei within the molecule. By mixing data obtained from these spectra, the characteristic peaks of the molecule can be identified clearly, and the molecular structure of the active end product can be confirmed.
Download application note for extended discussion on structural characterisation by NMR looking at Ibuprofen
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