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Toxins (Basel). 2012 Aug;4(8):580-604. Epub 2012 Jul 31.

Molecular motions as a drug target: mechanistic simulations of anthrax toxin edema factor function led to the discovery of novel allosteric inhibitors.

Author information

1
Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan, 61 Avenue du Président Wilson, 94235 Cachan Cedex, France. elodie.laine@lbpa.ens-cachan.fr

Abstract

Edema Factor (EF) is a component of Bacillus anthracis toxin essential for virulence. Its adenylyl cyclase activity is induced by complexation with the ubiquitous eukaryotic cellular protein, calmodulin (CaM). EF and its complexes with CaM, nucleotides and/or ions, have been extensively characterized by X-ray crystallography. Those structural data allowed molecular simulations analysis of various aspects of EF action mechanism, including the delineation of EF and CaM domains through their association energetics, the impact of calcium binding on CaM, and the role of catalytic site ions. Furthermore, a transition path connecting the free inactive form to the CaM-complexed active form of EF was built to model the activation mechanism in an attempt to define an inhibition strategy. The cavities at the surface of EF were determined for each path intermediate to identify potential sites where the binding of a ligand could block activation. A non-catalytic cavity (allosteric) was found to shrink rapidly at early stages of the path and was chosen to perform virtual screening. Amongst 18 compounds selected in silico and tested in an enzymatic assay, 6 thiophen ureidoacid derivatives formed a new family of EF allosteric inhibitors with IC50 as low as 2 micromolars.

KEYWORDS:

Edema factor; allostery; anthrax; molecular modeling; transition path; virtual screening

PMID:
23012649
PMCID:
PMC3446745
DOI:
10.3390/toxins4080580
[Indexed for MEDLINE]
Free PMC Article
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