A theoretical study of anthrax lethal factor inhibition by a set of novel carbamimidolyl-aryl-vinyl-carboxamidines: A possible mechanism involving zinc-ligation by amidine

作者：Nguyen Tam Luong; Panchal Rekha G; Topol Igor A; Lane Douglas; Kenny Tara; Burnett James C; Hermone Ann R; McGrath Connor; Burt Stanley K; Gussio Rick; Bavari Sina^*

来源：Journal of Molecular Structure (Theochem), 2007, 821(1-3): 139-144.

DOI：10.1016/j.theochem.2007.07.009

• three-dimensional search query
• density functional theory
• docking study
• molecular dynamics
• zinc coordination

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 pK(a) of the amidine functionality when it is in close proximity to zinc, thus allowing for the formation of a robust zinc-amidine bond. Published by Elsevier B.V.

• 出版日期2007-11-1