title: Identification of a small molecule beta-secretase inhibitor that binds without catalytic aspartate engagement.
abstract: A small molecule inhibitor of beta-secretase with a unique binding mode has been developed. Crystallographic determination of the enzyme-inhibitor complex shows the catalytic aspartate residues in the active site are not engaged in inhibitor binding. This unprecedented binding mode in the field of aspartyl protease inhibition is described.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co, West Point, PA 19486, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Steele
authors.forename: Ivory D
authors.initials: ID
authors.lastname: Hills
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Nomland
authors.forename: Pablo
authors.initials: P
authors.lastname: de León
authors.forename: Timothy
authors.initials: T
authors.lastname: Allison
authors.forename: Georgia
authors.initials: G
authors.lastname: McGaughey
authors.forename: Dennis
authors.initials: D
authors.lastname: Colussi
authors.forename: Katherine
authors.initials: K
authors.lastname: Tugusheva
authors.forename: Sharie J
authors.initials: SJ
authors.lastname: Haugabook
authors.forename: Amy S
authors.initials: AS
authors.lastname: Espeseth
authors.forename: Paul
authors.initials: P
authors.lastname: Zuck
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Stachel
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001224:Aspartic Acid; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D011485:Protein Binding
chemical_list: D004791:Enzyme Inhibitors; D001224:Aspartic Acid; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases