Fragment-based discovery of BACE1 inhibitors using functional assays.
Novel nonpeptidic inhibitors of beta-secretase (BACE1) have been discovered by employing a fragment-based biochemical screening approach. A diverse library of 20000 low-molecular weight compounds were screened and yielded 26 novel hits that were confirmed by biochemical and surface plasmon resonance secondary assays. We describe here fragment inhibitors cocrystallized with BACE1 in a flap open and flap closed conformation as determined by X-ray crystallography.
Evotec AG, Schnackenburgallee 114, 22525 Hamburg, Germany. robert.godemann@evotec.com
Robert
R
Godemann
James
J
Madden
Joachim
J
Krämer
Myron
M
Smith
Ulrike
U
Fritz
Thomas
T
Hesterkamp
John
J
Barker
Sabine
S
Höppner
David
D
Hallett
Andrea
A
Cesura
Andreas
A
Ebneth
John
J
Kemp
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*
D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human