Beta-secretase (BACE-1) inhibitors: accounting for 10s loop flexibility using rigid active sites

Bioorg Med Chem Lett. 2007 Feb 15;17(4):1117-21. doi: 10.1016/j.bmcl.2006.11.003. Epub 2006 Nov 6.


BACE-1 is a flexible enzyme with experimentally determined motion in the flap region, the catalytic aspartates, and the 10s loop. Four in-house crystallographically determined complexes of tertiary carbinamine inhibitors revealed 10s loop motion in the S(3) pocket. These X-ray structures were used to correlate K(i) values, which span over five orders of magnitude, with the calculated interaction energy, using the Merck Molecular Force Field for a series of 19 tertiary carbinamine inhibitors.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Aspartic Acid / analogs & derivatives
  • Aspartic Acid / chemistry
  • Aspartic Acid / pharmacology
  • Binding Sites
  • Catalysis
  • Chemical Phenomena
  • Chemistry, Physical
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Ligands
  • Molecular Conformation
  • Structure-Activity Relationship
  • Thermodynamics


  • Enzyme Inhibitors
  • Ligands
  • Aspartic Acid
  • Amyloid Precursor Protein Secretases