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Discovery of new non-pyrimidine scaffolds as Plasmodium falciparum DHFR inhibitors by fragment-based screening
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Document Title
Discovery of new non-pyrimidine scaffolds as Plasmodium falciparum DHFR inhibitors by fragment-based screening
Author
Hoarau M., Vanichtanankul J., Srimongkolpithak N., Vitsupakorn D., Yuthavong Y., Kamchonwongpaisan S.
Name from Authors Collection
Affiliations
National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathumthani, Thailand
Type
Article
Source Title
Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN
14756366
Year
2021
Volume
36
Issue
1
Page
198-206
Open Access
All Open Access, Gold
Publisher
Taylor and Francis Ltd.
DOI
10.1080/14756366.2020.1854244
Format
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 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. © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Industrial Classification
Knowledge Taxonomy Level 1
Knowledge Taxonomy Level 2
Knowledge Taxonomy Level 3
Funding Sponsor
Medicines for Malaria Venture; National Science and Technology Development Agency; National Center for Genetic Engineering and Biotechnology
Funding Number
P1450883, P1850116
License
N/A
Rights
N/A
Publication Source
Scopus
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Discovery of new non-pyrimidine scaffolds as Plasmodium falciparum DHFR inhibitors by fragment-based screeningDownload