NMR methods for characterising ligand-receptor and drug-membrane interactions in pharmaceutical research

A common strategy in drug discovery is to identify small molecules that interact with a specific target receptor and then to perform iterations of structural optimisation to produce high-affinity lead compounds to progress into pre-clinical development. The last decade has witnessed the development of several sensitive high-throughput NMR that have to rejuvenate NMR as a valuable tool for screening and characterising receptor-ligand interactions in the early stages of the drug discovery process. This chapter highlights the recent advances in NMR methods and technology that are now being implemented widely in pharmaceutical research for probing receptor-ligand interactions, and describes some of the emerging techniques that promise to be of value in the future. The NMR methods reviewed fall conveniently into two broad categories, namely, methods that detect the ligands and methods that observe the receptor target. Most of these methods can be implemented on conventional liquid-state spectrometers, but this chapter also draws attention to some recent examples of how solid-state NMR methods are providing information about ligand interactions with insoluble protein targets such as membrane-embedded receptors. It is also shown how NMR methods for characterising drug-membrane interactions are also proving useful in the structural optimisation of pharmaceutical lead compounds, as drug lipophilicity has implications for absorption, distribution and metabolism. The range of methods and their applications covered in this review, although not exhaustive, provide testament to the versatility of NMR, an advantage that will help to secure its future as an important and evolving technique in drug discovery.