Structural Insight into Effective Inhibitors' Binding to Dihydrofolate Reductase Thymidylate Synthase.

Pyrimethamine (Pyr), a known dihydrofolate reductase (DHFR) inhibitor, has long been used to treat toxoplasmosis caused by (Tg) infection. However, Pyr is effective only at high doses with associated toxicity to patients, calling for safer alternative treatments. In this study, we investigated a series of Pyr analogues, previously developed as DHFR inhibitors of bifunctional DHFR-thymidylate synthase (PfDHFR-TS), for their activity against DHFR-TS (TgDHFR-TS).