Virtual screening reveals allosteric inhibitors of the Toxoplasma gondii thymidylate synthase-dihydrofolate reductase

Bioorg Med Chem Lett. 2014 Feb 15;24(4):1232-5. doi: 10.1016/j.bmcl.2013.12.039. Epub 2013 Dec 31.

Abstract

The parasite Toxoplasma gondii can lead to toxoplasmosis in those who are immunocompromised. To combat the infection, the enzyme responsible for nucleotide synthesis thymidylate synthase-dihydrofolate reductase (TS-DHFR) is a suitable drug target. We have used virtual screening to determine novel allosteric inhibitors at the interface between the two TS domains. Selected compounds from virtual screening inhibited TS activity. Thus, these results show that allosteric inhibition by small drug-like molecules can occur in T. gondii TS-DHFR and pave the way for new and potent species-specific inhibitors.

Keywords: Dihydrofolate reductase; Thymidylate synthase; Toxoplasma gondii; Virtual screening.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Multienzyme Complexes / antagonists & inhibitors*
  • Multienzyme Complexes / metabolism
  • Structure-Activity Relationship
  • Tetrahydrofolate Dehydrogenase / metabolism
  • Thymidylate Synthase / antagonists & inhibitors*
  • Thymidylate Synthase / metabolism
  • Toxoplasma / enzymology*

Substances

  • Enzyme Inhibitors
  • Multienzyme Complexes
  • thymidylate synthase-dihydrofolate reductase
  • Tetrahydrofolate Dehydrogenase
  • Thymidylate Synthase