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

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