Novel inhibitors of anthrax edema factor

Deliang Chen, Milind Misra, Laurie Sower, Johnny W. Peterson, Glen E. Kellogg, Catherine H. Schein

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Several pathogenic bacteria produce adenylyl cyclase toxins, such as the edema factor (EF) of Bacillus anthracis. These disturb cellular metabolism by catalyzing production of excessive amounts of the regulatory molecule cAMP. Here, a structure-based method, where a 3D-pharmacophore that fit the active site of EF was constructed from fragments, was used to identify non-nucleotide inhibitors of EF. A library of small molecule fragments was docked to the EF-active site in existing crystal structures, and those with the highest HINT scores were assembled into a 3D-pharmacophore. About 10,000 compounds, from over 2.7 million compounds in the ZINC database, had a similar molecular framework. These were ranked according to their docking scores, using methodology that was shown to achieve maximum accuracy (i.e., how well the docked position matched the experimentally determined site for ATP analogues in crystal structures of the complex). Finally, 19 diverse compounds with the best AutoDock binding/docking scores were assayed in a cell-based assay for their ability to reduce cAMP secretion induced by EF. Four of the test compounds, from different structural groups, inhibited in the low micromolar range. One of these has a core structure common to phosphatase inhibitors previously identified by high-throughput assays of a diversity library. Thus, the fragment-based pharmacophore identified a small number of diverse compounds for assay, and greatly enhanced the selection process of advanced lead compounds for combinatorial design.

Original languageEnglish (US)
Pages (from-to)7225-7233
Number of pages9
JournalBioorganic and Medicinal Chemistry
Issue number15
StatePublished - Aug 1 2008


  • 3D-pharmacophore
  • Adenylyl cyclase inhibitor
  • Bacterial toxin inhibitor
  • Fragment docking
  • HINT program
  • Non-nucleotide ATP analogues
  • Structure-based screening

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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