A discovery of novel Mycobacterium tuberculosis pantothenate synthetase inhibitors based on the molecular mechanism of actinomycin D inhibition

Bioorg Med Chem Lett. 2011 Jul 1;21(13):3943-6. doi: 10.1016/j.bmcl.2011.05.021. Epub 2011 May 14.


Mycobacterium tuberculosis pantothenate synthetase is a potential anti-tuberculosis target, and a high-throughput screening system was previously developed to identify its inhibitors. Using a similar system, we screened a small library of compounds and identified actinomycin D (ActD) as a weak inhibitor of pantothenate synthetase. A new method was established to discover more effective inhibitors by determining the molecular mechanism of ActD inhibition followed by structure-based virtual screening. The molecular interaction of inhibition was determined by circular dichroism and tryptophan fluorescence quenching. The structure-based search and virtual screening were performed using the Molecular Operating Environment (MOE) program and SYBYL 7.5, respectively. Two inhibitors were identified with an IC(50) for pantothenate synthetase that was at least ten times better than that of ActD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / chemical synthesis*
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology
  • Dactinomycin / antagonists & inhibitors*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology*
  • Peptide Synthases / antagonists & inhibitors*
  • Small Molecule Libraries
  • Structure-Activity Relationship


  • Antitubercular Agents
  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Dactinomycin
  • Peptide Synthases
  • pantothenate synthetase