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

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

Author information

1
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
2
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Molecular Biophysics & Biochemistry, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
3
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520, USA.
4
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Molecular Biophysics & Biochemistry, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address: karen.anderson@yale.edu.

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

PMID:
24440298
PMCID:
PMC3946055
DOI:
10.1016/j.bmcl.2013.12.039
[Indexed for MEDLINE]
Free PMC Article

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