Virtual screening reveals allosteric inhibitors of the Toxoplasma gondii thymidylate synthase-dihydrofolate reductase.
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.
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Hitesh
H
Sharma
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.
Mark J
MJ
Landau
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520, USA.
Todd J
TJ
Sullivan
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Vidya P
VP
Kumar
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520, USA.
Markus K
MK
Dahlgren
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520, USA.
William L
WL
Jorgensen
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.
Karen S
KS
Anderson
D000494:Allosteric Regulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014122:Toxoplasma / Q000201:enzymology*
D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; C056930:thymidylate synthase-dihydrofolate reductase; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase
Dihydrofolate reductase; Thymidylate synthase; Toxoplasma gondii; Virtual screening