Fragment-based discovery (FBD) and structure-based design (SBD) have had a significant impact on the process of discovering and validating new chemical classes for protein targets that have long been considered 'undruggable'. Membrane proteins such as GPCRs and ion channels represent a more druggable class of protein target, and have been heavily exploited using standard methods such as High Throughput Screening (HTS). Recent advances have enabled the application of FBD and SBD tools to this important class of drug target in ways that can fundamentally change the way that compounds are identified and optimized. In particular, Nuclear Magnetic Resonance (NMR) spectroscopy is applicable as it provides opportunities for characterizing protein-ligand interactions in a highly dynamic environment.<br/><br/>This presentation will highlight newer methods to produce high-quality membrane proteins in a system that faithfully reproduces their native environment. In addition, NMR strategies will be highlighted that bypass the need for full characterization of the proteins but provide information that is useful for the discovery of new therapeutics targeting membrane proteins. These include understanding binding of known ligands, competitive displacement of stable isotope-labeled ligands, placement of discrete stable isotope labels in membrane proteins, and full reconstitution of integral and peripheral membrane proteins for structural characterization.

NMR tools for drug discovery: Targeting membrane proteins

254th National Meeting (2017)

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