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

Bioorg Med Chem Lett. 2009 Jun 15;19(12):3188-92. doi: 10.1016/j.bmcl.2009.04.113. Epub 2009 May 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Catalytic Domain
  • Computer Simulation
  • Drug Evaluation, Preclinical / methods*
  • Fluorescence Resonance Energy Transfer
  • Humans
  • Inhibitory Concentration 50
  • Organic Chemicals / pharmacology
  • Protein Binding

Substances

  • Organic Chemicals
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human