Novel non-peptide beta-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 beta-secretase (BACE-1). Fifteen hits with inhibitory potencies ranging from 2.8 to 118 microM (IC(50)) against beta-secretase were successfully identified. Compound 12 with IC(50) of 2.8 microM 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.