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 <sup>19sup>F NMR-based methods has been shown to provide several advantages over <sup>1sup>H NMR using traditional magnetization-transfer and/or two-dimensional methods. Here, we demonstrate the utility and power of <sup>19sup>F-based fragment screening by detailing the identification of a second-site fragment through <sup>19sup>F 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.