Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors

Xiaoyi Deng, Sreekanth Kokkonda, Farah El Mazouni, John White, Jeremy N. Burrows, Werner Kaminsky, Susan A. Charman, David Matthews, Pradipsinh K. Rathod, Margaret A. Phillips

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)5381-5394
Number of pages14
JournalJournal of Medicinal Chemistry
Volume57
Issue number12
DOIs
StatePublished - Jun 26 2014

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Fluorine
Plasmodium falciparum
Ligands
Plasmodium
Halogenation
Antimalarials
Enzymes
Hydrocarbons
Hydrophobic and Hydrophilic Interactions
Autoimmune Diseases
Malaria
Communicable Diseases
Hydrogen
Proteins
Binding Sites
Drug Therapy
dihydroorotate dehydrogenase

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors. / Deng, Xiaoyi; Kokkonda, Sreekanth; El Mazouni, Farah; White, John; Burrows, Jeremy N.; Kaminsky, Werner; Charman, Susan A.; Matthews, David; Rathod, Pradipsinh K.; Phillips, Margaret A.

In: Journal of Medicinal Chemistry, Vol. 57, No. 12, 26.06.2014, p. 5381-5394.

Research output: Contribution to journalArticle

Deng, X, Kokkonda, S, El Mazouni, F, White, J, Burrows, JN, Kaminsky, W, Charman, SA, Matthews, D, Rathod, PK & Phillips, MA 2014, 'Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors', Journal of Medicinal Chemistry, vol. 57, no. 12, pp. 5381-5394. https://doi.org/10.1021/jm500481t
Deng, Xiaoyi ; Kokkonda, Sreekanth ; El Mazouni, Farah ; White, John ; Burrows, Jeremy N. ; Kaminsky, Werner ; Charman, Susan A. ; Matthews, David ; Rathod, Pradipsinh K. ; Phillips, Margaret A. / Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 12. pp. 5381-5394.
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