7CTW

Wild-type Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with fragment 820, NADPH, dUMP

7CTW の概要

• エントリーDOI: 10.2210/pdb7ctw/pdb
• 分子名称: Bifunctional dihydrofolate reductase-thymidylate synthase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 1-(2-methylsulfanylphenyl)piperazine, ... (5 entities in total)
• 機能のキーワード: anti-folate, anti-malarial, plasmodium falciparum, dihydrofolate reductase, fragment, antibiotic, oxidoreductase
• 由来する生物種: Plasmodium falciparum (malaria parasite P. falciparum)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 145450.14

構造登録者

Vanichtanankul, J.,Vitsupakorn, D. (登録日: 2020-08-20, 公開日: 2021-04-28, 最終更新日: 2023-11-29)

主引用文献

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

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: 33530764
DOI: 10.1080/14756366.2020.1854244

実験手法

X-RAY DIFFRACTION (2.51 Å)