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

Jordan JB et al., 59: 3732-3749, J Med Chem, 2016

The aspartic acid protease, β-secretase (BACE-1) is a key target implicated in the pathogenesis of Alzheimer's disease (AD). Demonstrated herein is the utility of 19F-NMR Spectroscopy to identify highly potent and selective small-molecule inhibitors of BACE-1 using a method based on fragment-linking. The binding of synthesized compounds (6-9) to BACE-1 was studied by Surface Plasmon Resonance (SPR) spectroscopy using Pall ForteBio Pioneer FE system and Biacore S51. Glycosylated BACE-1 was treated with sodium periodate to oxidize cis-diol groups to aldehydes. The oxidized BACE-1 was covalently immobilized onto COOH5 sensor chip using aldehyde coupling chemistry. Subsequently, compounds (6-9) were serially diluted in running buffer and injected over the immobilized BACE-1. KD values were determined for all binding interactions. Overall results of this investigation suggest that 19F NMR based fragment-linking approach could be a powerful tool in fragment-based drug discovery.

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