Fragment Based Drug Discovery: Practical Implementation Based on 19F NMR Spectroscopy

• Published in: Journal of medicinal chemistry 2012-01, Vol.55 (2), p.678-687
• Main Authors: Jordan, John B, Poppe, Leszek, Xia, Xiaoyang, Cheng, Alan C, Sun, Yax, Michelsen, Klaus, Eastwood, Heather, Schnier, Paul D, Nixey, Thomas, Zhong, Wenge
• Format: Article
• Language: English
• Subjects: Aminoquinolines - chemistry; Amyloid Precursor Protein Secretases - chemistry; Databases, Factual; Drug Design; Fluorine; Magnetic Resonance Spectroscopy; Quantitative Structure-Activity Relationship; Surface Plasmon Resonance
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm201441k

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 1H–15N heteronuclear single quantum coherence (HSQC) as well as one-dimensional 1H and 19F 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 19F 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 19F 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.