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.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas , 6001 Forest Park Boulevard, Dallas, Texas 75390-9041, United States.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Deng
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Kokkonda
authors.forename: Farah
authors.initials: F
authors.lastname: El Mazouni
authors.forename: John
authors.initials: J
authors.lastname: White
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Burrows
authors.forename: Werner
authors.initials: W
authors.lastname: Kaminsky
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: David
authors.initials: D
authors.lastname: Matthews
authors.forename: Pradipsinh K
authors.initials: PK
authors.lastname: Rathod
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D000090722:Dihydroorotate Dehydrogenase; D004285:Dogs; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D011743:Pyrimidines; D013844:Thiazoles; D044925:Oxidoreductases Acting on CH-CH Group Donors