β-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 S3 pocket. These X-ray structures were used to correlate Ki 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.

Graphical abstractBACE-1 crystal structures demonstrating 10s loop motion were used to correlate Ki values from a series of tertiary carbinamine inhibitors with an empirical scoring function.Figure optionsDownload full-size imageDownload as PowerPoint slide