ArticleJournal of medicinal chemistry2014
Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors.
Article in Journal of medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
33 citing papers in PubMed, 109 citations in OpenAlex.
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- Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistantProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Fluorinated Protein and Peptide Materials for Biomedical Applications.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.Journal of medicinal chemistry · 2021Article
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- An insight on medicinal attributes of 1,2,4-triazoles.European journal of medicinal chemistry · 2020Review
- Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria.Journal of medicinal chemistry · 2020Article
- Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism.Cell chemical biology · 2020Article
- Synthesis and Antiplasmodial Activity of 1,2,3-Triazole-Naphthoquinone Conjugates.Molecules (Basel, Switzerland) · 2019Article
- Identification and Mechanistic Understanding of Dihydroorotate Dehydrogenase Point Mutations in Plasmodium falciparum that Confer in Vitro Resistance to the Clinical Candidate DSM265.ACS infectious diseases · 2019Article
- Open-source discovery of chemical leads for next-generation chemoprotective antimalarials.Science (New York, N.Y.) · 2018Article
- Isoxazolopyrimidine-Based Inhibitors ofACS omega · 2018Article
- Biosynthesis of Fluorinated Peptaibols Using a Site-Directed Building Block Incorporation Approach.Journal of natural products · 2017Article
- Discovery of Antimalarial Azetidine-2-carbonitriles That InhibitACS medicinal chemistry letters · 2017Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
Abstract
Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. We describe a detailed analysis of protein-ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series to explore the effects of fluorine on affinity and species selectivity. We show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. We conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. Our studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.