Beta-secretase (BACE-1) inhibitors: accounting for 10s loop flexibility using rigid active sites

Georgia B McGaughey; Dennis Colussi; Samuel L Graham; Ming-Tain Lai; Sanjeev K Munshi; Philippe G Nantermet; Beth Pietrak; Hemaka A Rajapakse; Harold G Selnick; Shaun R Stauffer; M Katharine Holloway

doi:10.1016/j.bmcl.2006.11.003

Beta-secretase (BACE-1) inhibitors: accounting for 10s loop flexibility using rigid active sites

Bioorg Med Chem Lett. 2007 Feb 15;17(4):1117-21. doi: 10.1016/j.bmcl.2006.11.003. Epub 2006 Nov 6.

Authors

Georgia B McGaughey¹, Dennis Colussi, Samuel L Graham, Ming-Tain Lai, Sanjeev K Munshi, Philippe G Nantermet, Beth Pietrak, Hemaka A Rajapakse, Harold G Selnick, Shaun R Stauffer, M Katharine Holloway

Affiliation

¹ Department of Molecular Systems, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. georgia_mcgaughey@merck.com

PMID: 17112725
DOI: 10.1016/j.bmcl.2006.11.003

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.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Aspartic Acid / analogs & derivatives
Aspartic Acid / chemistry
Aspartic Acid / pharmacology
Binding Sites
Catalysis
Chemical Phenomena
Chemistry, Physical
Crystallography, X-Ray
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Ligands
Molecular Conformation
Structure-Activity Relationship
Thermodynamics

Substances

Enzyme Inhibitors
Ligands
Aspartic Acid
Amyloid Precursor Protein Secretases