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

Journal of Enzyme Inhibition and Medicinal Chemistry

Marie Hoarau¹  Sumalee Kamchonwongpaisan¹  Jarunee Vanichtanankul¹  Nitipol Srimongkolpithak¹  Danoo Vitsupakorn¹  Yongyuth Yuthavong¹ 

[1] National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency;

关键词: malaria;    plasmodium falciparum;    fragment-based screening;    dihydrofolate reductase;    small molecule inhibitors;   

DOI  :  10.1080/14756366.2020.1854244

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown