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

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 IC50 for pantothenate synthetase that was at least ten times better than that of ActD.

Graphical abstractMycobacterium tuberculosis pantothenate synthetase (MTB PS) is a potential anti-tuberculosis target. Using a high-throughput screening system, we found actinomycin D (ActD) as a weak inhibitor of pantothenate synthestase. The interaction of ActD and MTB PS was determined by circular dichroism, fluorescence quenching and autodock. Two novel inhibitors of pantothenate synthetase were found based on the interaction between MTB PS and ActD followed by structure-based virtual screening.Figure optionsDownload full-size imageDownload as PowerPoint slide