| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 5417783 | Journal of Molecular Structure: THEOCHEM | 2007 | 6 Pages |
Abstract
A congeneric set of carbamimidolyl-aryl-vinyl-carboxamidines from the National Cancer Institute (NCI) open chemical repository were identified as potent inhibitors of anthrax lethal factor (LF), a zinc-dependent metalloprotease that plays a critical role in potentiating Bacillus anthracis infection. Surprisingly, these compounds exhibited no differential change in activity with concentration. Docking studies revealed that the indole-attached amidine substituents of these inhibitors were positioned in close proximity to the biological zinc atom and could potentially function as transition-state mimetics. This broaches the stunning possibility that the dose independence of these inhibitors is linked to zinc-ligation. Because the amidine functionality is highly basic and cationic, it is generally not considered a viable zinc-binding motif. However, quantum chemical calculations on small-molecule models predicted a marked decrease in the pKa of the amidine functionality when it is in close proximity to zinc, thus allowing for the formation of a robust zinc-amidine bond.
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Authors
Tam Luong Nguyen, Rekha G. Panchal, Igor A. Topol, Douglas Lane, Tara Kenny, James C. Burnett, Ann R. Hermone, Connor McGrath, Stanley K. Burt, Rick Gussio, Sina Bavari,