9XIO
Toxoplasma gondii dihydrofolate reductase thymidylate synthase (TgDHFR-TS) complexed with P218, NADPH and dUMP
Summary for 9XIO
| Entry DOI | 10.2210/pdb9xio/pdb |
| Descriptor | Bifunctional dihydrofolate reductase-thymidylate synthase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 3-(2-{3-[(2,4-diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)propanoic acid, ... (5 entities in total) |
| Functional Keywords | dihydrofolate reductase, toxoplasma gondii, p218, oxidoreductase |
| Biological source | Toxoplasma gondii |
| Total number of polymer chains | 4 |
| Total formula weight | 281018.60 |
| Authors | Vanichtanankul, J.,Saeyang, T.,Yuthavong, Y.,Kamchonwongpaisan, S. (deposition date: 2025-11-03, release date: 2026-09-16) |
| Primary citation | Decharuangsilp, S.,Koompapong, K.,Arwon, U.,Tuyapala, N.,Hoarau, M.,Tanasugarn, L.,Pengon, J.,Talawanich, Y.,Saeyang, T.,Vanichtanankul, J.,Yuthavong, Y.,Kamchonwongpaisan, S.,Mahittikorn, A.,Kongkasuriyachai, D. Repurpose antimalarials to target Toxoplasma gondii dihydrofolate reductase thymidylate synthase. Eur.J.Med.Chem., 313:118863-118863, 2026 Cited by PubMed Abstract: Toxoplasma gondii is an obligate intracellular blood and tissue protozoan parasite that infects up to a third of the population worldwide. Several antimalarial drugs, in particular pyrimethamine (PYR), have been used for decades to treat toxoplasmosis. Here, the clinical candidate P218, a potent inhibitor of Plasmodium falciparum dihydrofolate reductase (PfDHFR), and a series of flexible diaminopyrimidine butyrolactone analogues were identified as potent T. gondii dihydrofolate reductase (TgDHFR) inhibitors. The most promising butyrolactone analogue, LA4, displayed an improved TgDHFR inhibition (K 1.71 nM), increased antiparasitic properties in vitro (IC 0.44 nM), and a higher cell selectivity compared to PYR (K 13.0 nM, IC 410 nM) while P218 (K 2.19 nM, IC 370 nM) presented an improved activity with comparable cell selectivity to PYR. The in vivo results against T. gondii RH strain-infected mice showed that P218 reduced parasitic burden in blood whereas LA4 decreased parasite load in peritoneal fluid and blood with an extended mice survival. These findings position butyrolactone LA4 as a new potential for the treatment of acute toxoplasmosis. PubMed: 42060965DOI: 10.1016/j.ejmech.2026.118863 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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