Fragment Based Drug Discovery: Practical Implementation Based On F-19 Nmr Spectroscopy

Fragment based drug discovery (FBDD) is a widely used tool for discovering novel therapeutics. NMR is a powerful means for implementing FBDD, and several approaches have been proposed utilizing H-1-N-15 heteronuclear single quantum coherence (HSQC) as well as one-dimensional H-1 and F-19 NMR to screen compound mixtures against a target of interest. While proton-based NMR methods of fragment screening (FBS) have been well documented and are widely used, the use of F-19 detection in FBS has been only recently introduced (Vulpetti et al. J. Am. Chem. Soc. 2009, 131 (36), 12949-12959) with the aim of targeting "fluorophilic" sites in proteins. Here, we demonstrate a more general use of F-19 NMR-based fragment screening in several areas: as a key tool for rapid and sensitive detection of fragment hits, as a method for the rapid development of structure-activity relationship (SAR) on the hit-to-lead path using in-house libraries and/or commercially available compounds, and as a quick and efficient means of assessing target druggability.