title: Design, synthesis and X-ray structure of protein-ligand complexes: important insight into selectivity of memapsin 2 (beta-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.
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA. akghosh@purdue.edu
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Nagaswamy
authors.initials: N
authors.lastname: Kumaragurubaran
authors.forename: Lin
authors.initials: L
authors.lastname: Hong
authors.forename: Hui
authors.initials: H
authors.lastname: Lei
authors.forename: Khaja Azhar
authors.initials: KA
authors.lastname: Hussain
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Liu
authors.forename: Thippeswamy
authors.initials: T
authors.lastname: Devasamudram
authors.forename: Vajira
authors.initials: V
authors.lastname: Weerasena
authors.forename: Robert
authors.initials: R
authors.lastname: Turner
authors.forename: Gerald
authors.initials: G
authors.lastname: Koelsch
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Bilcer
authors.forename: Jordan
authors.initials: J
authors.lastname: Tang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011506:Proteins / Q000737:chemistry*
chemical_list: D008024:Ligands; D011480:Protease Inhibitors; D011506:Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human