Predictive modeling targets thymidylate synthase ThyX in Mycobacterium tuberculosis

  • Kamel Djaout, Vinayak Singh, Yap Boum, Victoria Katawera, Hubert F. Becker, Natassja G. Bush, Stephen J. Hearnshaw, Jennifer E. Pritchard, Pauline Bourbon, Peter B. Madrid, Anthony Maxwell, Valerie Mizrahi, Hannu Myllykallio, Sean Ekins
  • Scientific Reports, June 2016, Nature Publishing Group
  • DOI: 10.1038/srep27792

Finding Mtb ThyX inhibitors

What is it about?

The current study set out to understand the structure-activity relationships of ThyX in Mtb using a combination of cheminformatics and in vitro screening. We report the identification of new Mtb ThyX inhibitors, 2-chloro-3-(4-methanesulfonylpiperazin-1-yl)-1,4-dihydronaphthalene-1,4-dione) and idebenone.

Why is it important?

We show how similarity searching, pharmacophores and machine learning can be used with ThyX. ThyX is an essential thymidylate synthase (TS) that is both mechanistically and structurally unrelated to the analogous human enzyme. We started with napthoquinones and looked at overlap of compounds with GyrX. We had more success with finding new compounds for ThyX than Gyr.

Perspectives

Dr Sean Ekins
Collaborations in Chemistry

An international collaboration with groups in France, UK, South Africa, Uganda and the USA. What started as from the overlap of napthoquinones having some overlap in activity for ThyX and Gyr lead to a study including computational and experimental testing.

Read Publication

http://dx.doi.org/10.1038/srep27792

The following have contributed to this page: Dr Sean Ekins