title: Identification of a small molecule nonpeptide active site beta-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases.
abstract: A small molecule nonpeptide inhibitor of beta-secretase has been developed, and its binding has been defined through crystallographic determination of the enzyme-inhibitor complex. The molecule is shown to bind to the catalytic aspartate residues in an unprecedented manner in the field of aspartyl protease inhibition. Additionally, the complex reveals a heretofore unknown S(3) subpocket that is created by the inhibitor. This structure has served an important role in the design of newer beta-secretase inhibitors.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laoratories, West Point, PA 19486-0004, USA. craig_coburn@merck.com
authors.forename: Craig A
authors.initials: CA
authors.lastname: Coburn
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Stachel
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Li
authors.forename: Diane M
authors.initials: DM
authors.lastname: Rush
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Steele
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Chen-Dodson
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: Jillian
authors.initials: J
authors.lastname: DiMuzio
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Crouthamel
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Shi
authors.forename: Vinod
authors.initials: V
authors.lastname: Sardana
authors.forename: Zhongguo
authors.initials: Z
authors.lastname: Chen
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Munshi
authors.forename: Lawrence
authors.initials: L
authors.lastname: Kuo
authors.forename: Gergely M
authors.initials: GM
authors.lastname: Makara
authors.forename: D Allen
authors.initials: DA
authors.lastname: Annis
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Tadikonda
authors.forename: Huw M
authors.initials: HM
authors.lastname: Nash
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Tong
authors.initials: T
authors.lastname: Wang
mesh_terms: D000081:Acetamides / Q000737:chemistry*; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry*; D001549:Benzamides / Q000737:chemistry*; D001557:Benzenesulfonates / Q000737:chemistry*; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D010450:Endopeptidases; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D001549:Benzamides; D001557:Benzenesulfonates; D011480:Protease Inhibitors; C494715:benzyl 5-((((5-aminopentyl)amino)carbonyl)methoxy)3-(((alpha-methyl-4-fluorobenzyl)amino)carbonyl)benzenesulfonate; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases