title: 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.
authors.affiliation: Department of Molecular Structure, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States. jbjordan@amgen.com
authors.forename: John B
authors.initials: JB
authors.lastname: Jordan
authors.forename: Leszek
authors.initials: L
authors.lastname: Poppe
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Xia
authors.forename: Alan C
authors.initials: AC
authors.lastname: Cheng
authors.forename: Yax
authors.initials: Y
authors.lastname: Sun
authors.forename: Klaus
authors.initials: K
authors.lastname: Michelsen
authors.forename: Heather
authors.initials: H
authors.lastname: Eastwood
authors.forename: Paul D
authors.initials: PD
authors.lastname: Schnier
authors.forename: Thomas
authors.initials: T
authors.lastname: Nixey
authors.forename: Wenge
authors.initials: W
authors.lastname: Zhong
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry*; D016208:Databases, Factual; D015195:Drug Design; D005461:Fluorine; D009682:Magnetic Resonance Spectroscopy; D021281:Quantitative Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D000634:Aminoquinolines; D005461:Fluorine; D053829:Amyloid Precursor Protein Secretases