Identification of a small molecule nonpeptide active site beta-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases

J Med Chem. 2004 Dec 2;47(25):6117-9. doi: 10.1021/jm049388p.

Abstract

A small molecule nonpeptide inhibitor of beta-secretase has been developed, and its binding has been defined through crystallographic determination of the enzyme-inhibitor complex. The molecule is shown to bind to the catalytic aspartate residues in an unprecedented manner in the field of aspartyl protease inhibition. Additionally, the complex reveals a heretofore unknown S(3) subpocket that is created by the inhibitor. This structure has served an important role in the design of newer beta-secretase inhibitors.

MeSH terms

  • Acetamides / chemistry*
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases / chemistry*
  • Benzamides / chemistry*
  • Benzenesulfonates / chemistry*
  • Binding Sites
  • Combinatorial Chemistry Techniques
  • Crystallography, X-Ray
  • Endopeptidases
  • Hydrogen Bonding
  • Models, Molecular
  • Molecular Structure
  • Protease Inhibitors / chemistry*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Acetamides
  • Benzamides
  • Benzenesulfonates
  • Protease Inhibitors
  • benzyl 5-((((5-aminopentyl)amino)carbonyl)methoxy)3-(((alpha-methyl-4-fluorobenzyl)amino)carbonyl)benzenesulfonate
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases