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Fragment based drug discovery: practical implementation based on ¹⁹F NMR spectroscopy.

Abstract：

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

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Jordan JB,Poppe L,Xia X,Cheng AC,Sun Y,Michelsen K,Eastwood H,Schnier PD,Nixey T,Zhong W

doi

10.1021/jm201441k

subject

Has Abstract

pub_date

2012-01-26 00:00:00

pages

678-87

issue

2

eissn

0022-2623

issn

1520-4804

journal_volume

55

pub_type

杂志文章

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