Novel non-peptide β-secretase inhibitors derived from structure-based virtual screening and bioassay

This Letter describes an efficient approach by integrating virtual screening with bioassay technology for finding small organic inhibitors targeting β-secretase (BACE-1). Fifteen hits with inhibitory potencies ranging from 2.8 to 118 μM (IC50) against β-secretase were successfully identified. Compound 12 with IC50 of 2.8 μM is the most potent hit against BACE-1. Docking simulation from gold 3.0 suggests putative binding mode of 12 in BACE-1 and potential key pharmacophore groups for further designing of non-peptide compounds as more powerful inhibitors against BACE-1.

Graphical abstractFifteen new compounds with novel chemical skeleton have been successfully discovered as β-secretase inhibitors through molecular docking in combination with bioassay. Molecular docking reveals that the compounds, for example, compound 12 with IC50 value of 2.8 μM, spans the interaction through almost all the sub-sites of BACE-1.Figure optionsDownload full-size imageDownload as PowerPoint slide