5T0L
Crystal structure of Toxoplasma gondii TS-DHFR complexed with NADPH, dUMP, PDDF and 5-(4-(3,4-dichlorophenyl)piperazin-1-yl)pyrimidine-2,4-diamine (TRC-15)
Summary for 5T0L
| Entry DOI | 10.2210/pdb5t0l/pdb |
| Descriptor | Bifunctional dihydrofolate reductase-thymidylate synthase, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total) |
| Functional Keywords | toxoplasma gondii, dhfr, inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Toxoplasma gondii |
| Total number of polymer chains | 2 |
| Total formula weight | 132169.21 |
| Authors | Thomas, S.B.,Chen, Z.,Lu, H.,Li, Y. (deposition date: 2016-08-16, release date: 2016-09-28, Last modification date: 2023-10-04) |
| Primary citation | Welsch, M.E.,Zhou, J.,Gao, Y.,Yan, Y.,Porter, G.,Agnihotri, G.,Li, Y.,Lu, H.,Chen, Z.,Thomas, S.B. Discovery of Potent and Selective Leads against Toxoplasma gondii Dihydrofolate Reductase via Structure-Based Design. ACS Med Chem Lett, 7:1124-1129, 2016 Cited by PubMed Abstract: Current treatment of toxoplasmosis targets the parasite's folate metabolism through inhibition of dihydrofolate reductase (DHFR). The most widely used DHFR antagonist, pyrimethamine, was introduced over 60 years ago and is associated with toxicity that can be largely attributed to a similar affinity for parasite and human DHFR. Computational analysis of biochemical differences between and human DHFR enabled the design of inhibitors with both improved potency and selectivity. The approach described herein yielded TRC-19, a promising lead with an IC of 9 nM and 89-fold selectivity in favor of DHFR, as well as crystallographic data to substantiate methodology. Overall, 50% of synthesized designs met hit threshold criteria of IC < 10 μM and >2-fold selectivity favoring , further demonstrating the efficiency of our structure-based drug design approach. PubMed: 27994750DOI: 10.1021/acsmedchemlett.6b00328 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.13 Å) |
Structure validation
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