Design, synthesis and X-ray structure of protein-ligand complexes: important insight into selectivity of memapsin 2 (beta-secretase) inhibitors

J Am Chem Soc. 2006 Apr 26;128(16):5310-1. doi: 10.1021/ja058636j.

Abstract

Structure-based design, synthesis, and X-ray structure of protein-ligand complexes of memapsin 2 are described. The inhibitors are designed specifically to interact with S2- and S3-active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 6 has exhibited exceedingly potent inhibitory activity against memapsin 2 and selectivity over memapsin 1 (>3800-fold) and cathepsin D (>2500-fold). A protein-ligand crystal structure revealed cooperative interactions in the S2- and S3-active sites of memapsin 2. These interactions may serve as an important guide to design selectivity over memapsin 1 and cathepsin D.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Crystallography, X-Ray
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Proteins / chemistry*

Substances

  • Ligands
  • Protease Inhibitors
  • Proteins
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human