title: Structure-based design of highly selective β-secretase inhibitors: synthesis, biological evaluation, and protein-ligand X-ray crystal structure.
abstract: The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective β-secretase inhibitors are described. The inhibitors are designed specifically to interact with S(1)' active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 5 has exhibited exceedingly potent inhibitory activity (K(i) = 17 pM) and high selectivity over BACE 2 (>7000-fold) and cathepsin D (>250000-fold). A protein-ligand crystal structure revealed important molecular insight into these selectivities. These interactions may serve as an important guide to design selectivity over the physiologically important aspartic acid proteases.
authors.affiliation: Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States. akghosh@purdue.edu
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Kalapala
authors.initials: K
authors.lastname: Venkateswara Rao
authors.forename: Navnath D
authors.initials: ND
authors.lastname: Yadav
authors.forename: David D
authors.initials: DD
authors.lastname: Anderson
authors.forename: Navnath
authors.initials: N
authors.lastname: Gavande
authors.forename: Xiangping
authors.initials: X
authors.lastname: Huang
authors.forename: Simon
authors.initials: S
authors.lastname: Terzyan
authors.forename: Jordan
authors.initials: J
authors.lastname: Tang
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010795:Phthalic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D007211:Indoles; D008024:Ligands; D010795:Phthalic Acids; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases