Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors

• DOI: 10.1021/jm500481t
• Publication Date: 2014-05-07T11:38:40Z
• Authors: 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
• Keywords: Dihydroorotate Dehydrogenase; Binding selectivity

Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) an important target for antimalarial chemotherapy. We describe a detailed analysis protein-ligand interactions between DHODH and triazolopyrimidine-based inhibitor series to explore effects fluorine on affinity species selectivity. show that increasing fluorination dramatically increases binding mammalian DHODHs, leading loss Triazolopyrimidines bind DHODHs in overlapping but distinct sites. Key hydrogen-bond stacking underlying strong PfDHODH are absent enzymes. Increasing substitution leads increase entropic contribution binding, suggesting consequence enhanced hydrophobic effect upon apolar pocket. conclude hydrocarbons provide significant energy interactions. Our studies define requirements species-selective triazolopyrimidine scaffold can alternatively be tuned inhibit human DHODH, autoimmune