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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

  1. Author:
    Nguyen, T. L.
    Panchal, R. G.
    Topol, I. A.
    Lane, D.
    Kenny, T.
    Burnett, J. C.
    Hermone, A. R.
    McGrath, C.
    Burt, S. K.
    Gussio, R.
    Bavari, S.

  2. Author Address

    USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA. NCI, SAIC Frederick Inc, Target Struct Based Drug Discovery Grp, Frederick, MD 21702 USA. NCI, SAIC Frederick Inc, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. NCI, Target Struct Based Drug Discovery Grp, Informat Technol Branch, Dev Therapeut Program, Frederick, MD 21702 USA.;Bavari, S, USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA.;sina.bavari@amedd.army.mil
    1. Year: 2007
    2. Date: Nov
  2. Journal: Journal of Molecular Structure-theochem
    1. 821
    2. 1-3
    3. Pages: 139-144
  4. Type of Article: Article
  5. ISSN: 0166-1280
  1. 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 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.

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External Sources

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  2. DOI: 10.1016/j.theochem.2007.07.009
  3. View record in Web of Science®
  4. WOS: 000250652300018

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