Identification of a small molecule beta-secretase inhibitor that binds without catalytic aspartate engagement

Thomas G Steele; Ivory D Hills; Ashley A Nomland; Pablo de León; Timothy Allison; Georgia McGaughey; Dennis Colussi; Katherine Tugusheva; Sharie J Haugabook; Amy S Espeseth; Paul Zuck; Samuel L Graham; Shawn J Stachel

doi:10.1016/j.bmcl.2008.11.027

Identification of a small molecule beta-secretase inhibitor that binds without catalytic aspartate engagement

Bioorg Med Chem Lett. 2009 Jan 1;19(1):17-20. doi: 10.1016/j.bmcl.2008.11.027. Epub 2008 Nov 13.

Authors

Thomas G Steele¹, Ivory D Hills, Ashley A Nomland, Pablo de León, Timothy Allison, Georgia McGaughey, Dennis Colussi, Katherine Tugusheva, Sharie J Haugabook, Amy S Espeseth, Paul Zuck, Samuel L Graham, Shawn J Stachel

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co, West Point, PA 19486, USA.

PMID: 19036583
DOI: 10.1016/j.bmcl.2008.11.027

Abstract

A small molecule inhibitor of beta-secretase with a unique binding mode has been developed. Crystallographic determination of the enzyme-inhibitor complex shows the catalytic aspartate residues in the active site are not engaged in inhibitor binding. This unprecedented binding mode in the field of aspartyl protease inhibition is described.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Aspartic Acid Endopeptidases / antagonists & inhibitors
Aspartic Acid Endopeptidases / metabolism
Aspartic Acid*
Catalytic Domain
Crystallography, X-Ray
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacokinetics*
Protein Binding

Substances

Enzyme Inhibitors
Aspartic Acid
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases