7CTY
Wild type plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS), fragment 263, NADP+, dUMP
Summary for 7CTY
| Entry DOI | 10.2210/pdb7cty/pdb |
| Descriptor | Bifunctional dihydrofolate reductase-thymidylate synthase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, spiro[1H-2-benzofuran-3,4'-piperidine], ... (5 entities in total) |
| Functional Keywords | dihydrofolate reductase, plasmodium falciparum, antimalarial, antifolate, fragment, antibiotic, oxidoreductase |
| Biological source | Plasmodium falciparum (malaria parasite P. falciparum) |
| Total number of polymer chains | 2 |
| Total formula weight | 144969.87 |
| Authors | Vanichtanankul, J.,Vitsupakorn, D. (deposition date: 2020-08-20, release date: 2021-03-31, Last modification date: 2023-11-29) |
| Primary citation | Hoarau, M.,Vanichtanankul, J.,Srimongkolpithak, N.,Vitsupakorn, D.,Yuthavong, Y.,Kamchonwongpaisan, S. Discovery of new non-pyrimidine scaffolds as Plasmodium falciparum DHFR inhibitors by fragment-based screening. J Enzyme Inhib Med Chem, 36:198-206, 2021 Cited by PubMed Abstract: In various malaria-endemic regions, the appearance of resistance has precluded the use of pyrimidine-based antifolate drugs. Here, a three-step fragment screening was used to identify new non-pyrimidine dihydrofolate reductase (DHFR) inhibitors. Starting from a 1163-fragment commercial library, a two-step differential scanning fluorimetry screen identified 75 primary fragment hits. Subsequent enzyme inhibition assay identified 11 fragments displaying IC in the 28-695 μM range and selectivity for DHFR. In addition to the known pyrimidine, three new anti-DHFR chemotypes were identified. Fragments from each chemotype were successfully co-crystallized with DHFR, revealing a binding in the active site, in the vicinity of catalytic residues, which was confirmed by molecular docking on all fragment hits. Finally, comparison with similar non-hit fragments provides preliminary input on available growth vectors for future drug development. PubMed: 33530764DOI: 10.1080/14756366.2020.1854244 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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