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

A small molecule inhibitor of β-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.

The unique binding of 5 in the BACE1 active site without catalytic aspartate engagement is described.Figure optionsDownload as PowerPoint slide