title: Beta-secretase (BACE-1) inhibitors: accounting for 10s loop flexibility using rigid active sites.
abstract: 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.
authors.affiliation: Department of Molecular Systems, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. georgia_mcgaughey@merck.com
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
authors.forename: Dennis
authors.initials: D
authors.lastname: Colussi
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Munshi
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Nantermet
authors.forename: Beth
authors.initials: B
authors.lastname: Pietrak
authors.forename: Hemaka A
authors.initials: HA
authors.lastname: Rajapakse
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D001224:Aspartic Acid; D053829:Amyloid Precursor Protein Secretases