Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 25, Issue 21, Pages 4812-4819Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.06.082
Keywords
Amyloid; Beta secretase; Spiropiperidine; Magic methyl effect
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The IC50 of a beta-secretase (BACE-1) lead compound was improved similar to 200-fold from 11 mu M to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor. (C) 2015 Elsevier Ltd. All rights reserved.
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