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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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.