Discovery of new non-pyrimidine scaffolds as Plasmodium falciparum DHFR inhibitors by fragment-based screening.

Marie Hoarau, Jarunee Vanichtanankul, Nitipol Srimongkolpithak, Danoo Vitsupakorn, Yongyuth Yuthavong, Sumalee Kamchonwongpaisan

Journal of enzyme inhibition and medicinal chemistry 2021 Dec

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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 μM 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.

Citation

Marie Hoarau, Jarunee Vanichtanankul, Nitipol Srimongkolpithak, Danoo Vitsupakorn, Yongyuth Yuthavong, Sumalee Kamchonwongpaisan. Discovery of new non-pyrimidine scaffolds as Plasmodium falciparum DHFR inhibitors by fragment-based screening. Journal of enzyme inhibition and medicinal chemistry. 2021 Dec;36(1):198-206