7cty | pdb_00007cty

Wild type plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS), fragment 263, NADP+, dUMP

spinqualitylabelsall models 7cty, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7cty is a 2 chain structure with sequence from Plasmodium falciparum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.8Å Ligands: GF3, NDP, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q8I1R6_PLAF7 Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism (By similarity).[PIRNR:PIRNR000389] Publication Abstract from PubMed 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 Plasmodium falciparum dihydrofolate reductase (PfDHFR) 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 IC50 in the 28-695 muM range and selectivity for PfDHFR. In addition to the known pyrimidine, three new anti-PfDHFR chemotypes were identified. Fragments from each chemotype were successfully co-crystallized with PfDHFR, 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. Discovery of new non-pyrimidine scaffolds as Plasmodium falciparum DHFR inhibitors by fragment-based screening.,Hoarau M, Vanichtanankul J, Srimongkolpithak N, Vitsupakorn D, Yuthavong Y, Kamchonwongpaisan S J Enzyme Inhib Med Chem. 2021 Dec;36(1):198-206. doi:, 10.1080/14756366.2020.1854244. PMID:33530764 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydrofolate reductase 3D structures

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