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

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

Research output: Contribution to journalArticleResearchpeer-review

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
Pages (from-to)5381 - 5394
Number of pages14
JournalJournal of Medicinal Chemistry
Volume57
Issue number12
DOIs
Publication statusPublished - 2014

Cite this

Deng, Xiaoyi ; Kokkonda, Sreekanth ; El Mazouni, Farah ; White, John ; Burrows, Jeremy ; Kaminsky, Werner ; Charman, Susan Ann ; 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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title = "Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors",
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.",
author = "Xiaoyi Deng and Sreekanth Kokkonda and {El Mazouni}, Farah and John White and Jeremy Burrows and Werner Kaminsky and Charman, {Susan Ann} and David Matthews and Rathod, {Pradipsinh K} and Phillips, {Margaret A}",
year = "2014",
doi = "10.1021/jm500481t",
language = "English",
volume = "57",
pages = "5381 -- 5394",
journal = "Journal of Medicinal Chemistry",
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Deng, X, Kokkonda, S, El Mazouni, F, White, J, Burrows, J, 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

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; Kaminsky, Werner; Charman, Susan Ann; Matthews, David; Rathod, Pradipsinh K; Phillips, Margaret A.

In: Journal of Medicinal Chemistry, Vol. 57, No. 12, 2014, p. 5381 - 5394.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors

AU - Deng, Xiaoyi

AU - Kokkonda, Sreekanth

AU - El Mazouni, Farah

AU - White, John

AU - Burrows, Jeremy

AU - Kaminsky, Werner

AU - Charman, Susan Ann

AU - Matthews, David

AU - Rathod, Pradipsinh K

AU - Phillips, Margaret A

PY - 2014

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N2 - 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.

AB - 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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M3 - Article

VL - 57

SP - 5381

EP - 5394

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 12

ER -