Predictive modeling targets thymidylate synthase ThyX in Mycobacterium tuberculosis

Sci Rep. 2016 Jun 10:6:27792. doi: 10.1038/srep27792.


There is an urgent need to identify new treatments for tuberculosis (TB), a major infectious disease caused by Mycobacterium tuberculosis (Mtb), which results in 1.5 million deaths each year. We have targeted two essential enzymes in this organism that are promising for antibacterial therapy and reported to be inhibited by naphthoquinones. ThyX is an essential thymidylate synthase that is mechanistically and structurally unrelated to the human enzyme. DNA gyrase is a DNA topoisomerase present in bacteria and plants but not animals. The current study set out to understand the structure-activity relationships of these targets in Mtb using a combination of cheminformatics and in vitro screening. Here, we report the identification of new Mtb ThyX inhibitors, 2-chloro-3-(4-methanesulfonylpiperazin-1-yl)-1,4-dihydronaphthalene-1,4-dione) and idebenone, which show modest whole-cell activity and appear to act, at least in part, by targeting ThyX in Mtb.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism*
  • Bayes Theorem
  • DNA Gyrase / metabolism
  • Enzyme Inhibitors / analysis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Machine Learning
  • Models, Molecular*
  • Mycobacterium tuberculosis / enzymology*
  • Naphthoquinones / chemistry
  • Naphthoquinones / pharmacology
  • Thymidylate Synthase / antagonists & inhibitors
  • Thymidylate Synthase / chemistry
  • Thymidylate Synthase / metabolism*
  • Ubiquinone / analogs & derivatives
  • Ubiquinone / chemistry
  • Ubiquinone / pharmacology
  • User-Computer Interface


  • Bacterial Proteins
  • Enzyme Inhibitors
  • Naphthoquinones
  • Ubiquinone
  • Thymidylate Synthase
  • DNA Gyrase
  • idebenone