NMR in drug design

Abstract

The use of NMR as a tool to determine 3 dimensional protein solution structures, once a darling of the pharmaceutical industry, has largely given way to study of the interaction of prospective drugs with macromolecular targets. Many of these approaches involve ligand-centered studies, which have the advantage of speed and efficiency, but there are also many approaches that take directly from our learnings in macromolecular NMR and provide greater structural detail yet are still optimized for rapid turn-around of information. In the evolution of NMR in the pharmaceutical industry, the unique strengths of NMR to provide dynamic and atomic level information continue to be exploited to discover and design new drugs. Numerous methods have been developed over the past two decades that fall into the categories of fragment-based pre-lead discovery, ligand binding studies and qualitative structural screening.

Keywords: Chemical shift perturbation; Fragment-based drug design; Fragment-based screening; High-throughput screening; Hit validation; Inter-ligand NOE; Ligand binding; Ligand-observed; Ligand-protein interaction; Millamolecule; NMR spectroscopy; Saturation transfer difference; T2 difference; Target-observed; Temperature shift coefficients; WaterLOGSY.