Fragment-Linking Approach Using 19F NMR Spectroscopy To Obtain Highly Potent and Selective Inhibitors of β-Secretase

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• 作者：John B. Jordan ; Douglas A. Whittington ; Michael D. Bartberger ; E. Allen Sickmier ; Kui Chen ; Yuan Cheng ; Ted Judd
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 28, 2016
• 年：2016
• 卷：59
• 期：8
• 页码：3732-3749
• 全文大小：688K
• 年卷期：0
• ISSN：1520-4804

文摘

Fragment-based drug discovery (FBDD) has become a widely used tool in small-molecule drug discovery efforts. One of the most commonly used biophysical methods in detecting weak binding of fragments is nuclear magnetic resonance (NMR) spectroscopy. In particular, FBDD performed with ¹⁹F NMR-based methods has been shown to provide several advantages over ¹H NMR using traditional magnetization-transfer and/or two-dimensional methods. Here, we demonstrate the utility and power of ¹⁹F-based fragment screening by detailing the identification of a second-site fragment through ¹⁹F NMR screening that binds to a specific pocket of the aspartic acid protease, β-secretase (BACE-1). The identification of this second-site fragment allowed the undertaking of a fragment-linking approach, which ultimately yielded a molecule exhibiting a more than 360-fold increase in potency while maintaining reasonable ligand efficiency and gaining much improved selectivity over cathepsin-D (CatD). X-ray crystallographic studies of the molecules demonstrated that the linked fragments exhibited binding modes consistent with those predicted from the targeted screening approach, through-space NMR data, and molecular modeling.