A Density Functional Study of the Inhibition of the Anthrax Lethal Factor Toxin by Quinoline-based small Molecules related to Aminoquinuride (NSC 12155).
We carried out an analysis of the relationships between the electronic structure of a series of 4,6-diamino-2-methylquinoline C-6 amides related to aminoquinuride and their inhibition of the anthrax lethal factor (LF) toxin,using a model-based method. The electronic structure of all the molecules was calculated at the B3LYP/6-31g(d,p) level of theory with full geometry optimization. Linear multiple regression analysis was employed to find the best relationship between anti-LF and local atomic reactivity indices belonging to a common skeleton. The variation of the anti-LF activity is related to the variation of a set of three specific local atomic reactivity indices. A 2D partial inhibitory pharmacophore is proposed. By analyzing the process leading to a failed prediction of a molecule with a higher anti-LF activity, we show the superiority of the model-based method used here.