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.
Godemann
Robert
R
Evotec AG, Schnackenburgallee 114, 22525 Hamburg, Germany. robert.godemann@evotec.com
Madden
James
J
Krämer
Joachim
J
Smith
Myron
M
Fritz
Ulrike
U
Hesterkamp
Thomas
T
Barker
John
J
Höppner
Sabine
S
Hallett
David
D
Cesura
Andrea
A
Ebneth
Andreas
A
Kemp
John
J
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