Design, Synthesis and X-ray Structure of Protein−Ligand Complexes: Important Insight into Selectivity of Memapsin 2 (β-Secretase) Inhibitors

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.