Identification of a small molecule beta-secretase inhibitor that binds without catalytic aspartate engagement.
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.
Steele
Thomas G
TG
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co, West Point, PA 19486, USA.
Hills
Ivory D
ID
Nomland
Ashley A
AA
de León
Pablo
P
Allison
Timothy
T
McGaughey
Georgia
G
Colussi
Dennis
D
Tugusheva
Katherine
K
Haugabook
Sharie J
SJ
Espeseth
Amy S
AS
Zuck
Paul
P
Graham
Samuel L
SL
Stachel
Shawn J
SJ
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
D004791:Enzyme Inhibitors; D001224:Aspartic Acid; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases