Beta-secretase (BACE-1) inhibitors: accounting for 10s loop flexibility using rigid active sites.
BACE-1 is a flexible enzyme with experimentally determined motion in the flap region, the catalytic aspartates, and the 10s loop. Four in-house crystallographically determined complexes of tertiary carbinamine inhibitors revealed 10s loop motion in the S(3) pocket. These X-ray structures were used to correlate K(i) values, which span over five orders of magnitude, with the calculated interaction energy, using the Merck Molecular Force Field for a series of 19 tertiary carbinamine inhibitors.
McGaughey
Georgia B
GB
Department of Molecular Systems, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. georgia_mcgaughey@merck.com
Colussi
Dennis
D
Graham
Samuel L
SL
Lai
Ming-Tain
MT
Munshi
Sanjeev K
SK
Nantermet
Philippe G
PG
Pietrak
Beth
B
Rajapakse
Hemaka A
HA
Selnick
Harold G
HG
Stauffer
Shaun R
SR
Holloway
M Katharine
MK
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002384:Catalysis; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D004791:Enzyme Inhibitors; D008024:Ligands; D001224:Aspartic Acid; D053829:Amyloid Precursor Protein Secretases