AI Article Synopsis
- * Used techniques like computational chemistry, small molecule NMR, and protein crystallography to analyze how the ligand’s shape changes with pH and when it’s bound to the enzyme.
- * The methyl group helped retain the necessary pKa for the piperidine nitrogen, filled a hydrophobic pocket, and stabilized the best conformation for effective receptor binding.
Article Abstract
The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 μM 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.
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| http://dx.doi.org/10.1016/j.bmcl.2015.06.082 | DOI Listing |
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