The NMR “Toolkit” for Compound Characterization

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This chapter discusses the application of various nuclear magnetic resonance (NMR) spectroscopy techniques to the process of drug discovery. To make it easier to understand how drug discovery incorporates NMR data, all drug discovery–related activities have been categorized into one of the following six disciplines: (1) natural products research; (2) medicinal chemistry; (3) rational drug design (protein structure and modeling); (4) metabolism; (5) combinatorial chemistry, and; (6) drug production and quality control. Although this classification process may initially appear to be somewhat artificial, its use makes it easier to understand the applications and advantages of each NMR technique. However, readers should recognize that most drug discovery programs involve a blend of these six disciplines and therefore usually benefit from using a combination of different NMR techniques. Most advances in NMR technology have occurred when someone tried to address a particular limitation in one of these six disciplines. However, once a new tool is developed, it can sometimes solve a different problem in a different discipline or spawn a whole new field of NMR. An example of the former is the use of magic-angle spinning first for solid-state NMR, then for small-volume solutionstate NMR for natural products, and then for solid-phase synthesis resin NMR for combinatorial chemistry. An example of the latter is the development of indirect detection, which helped spawn the use of isotopically labeled proteins and tripleresonance NMR for determining the structures of biomolecules in rational drug design programs.