7CTZ
Wild-type plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with fragment 148, NADPH, and dUMP
Summary for 7CTZ
| Entry DOI | 10.2210/pdb7ctz/pdb |
| Descriptor | Bifunctional dihydrofolate reductase-thymidylate synthase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, ... (5 entities in total) |
| Functional Keywords | anti-folate, anti-malarial, plasmodium falciparum, dihydrofolate reductase, antibiotic, oxidoreductase |
| Biological source | Plasmodium falciparum (malaria parasite P. falciparum) |
| Total number of polymer chains | 2 |
| Total formula weight | 145967.36 |
| Authors | Vitsupakorn, D. (deposition date: 2020-08-20, release date: 2022-02-23, 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 (2.65 Å) |
Structure validation
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