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

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• 作者：John B. Jordan ; Leszek Poppe ; Xiaoyang Xia ; Alan C. Cheng ; Yax Sun ; Klaus Michelsen ; Heather Eastwood ; Paul D. Schnier ; Thomas Nixey ; Wenge Zhong
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January 26, 2012
• 年：2012
• 卷：55
• 期：2
• 页码：678-687
• 全文大小：487K
• 年卷期：v.55,no.2(January 26, 2012)
• ISSN：1520-4804

文摘

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鈥?sup>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鈥?2959) with the aim of targeting 鈥渇luorophilic鈥?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鈥揳ctivity 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.