4OQV

High resolution crystal structure of human dihydroorotate dehydrogenase bound with DSM338 (N-[3,5-difluoro-4-(trifluoromethyl)phenyl]-5-methyl-2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine)

Summary for 4OQV

• Entry DOI: 10.2210/pdb4oqv/pdb
• Related: 4ORI 4ORM
• Descriptor: Dihydroorotate dehydrogenase (quinone), mitochondrial, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (9 entities in total)
• Functional Keywords: alpha/beta barrel, redox, dehydrogenase, fmn, mitochondrial membrane, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion inner membrane; Single-pass membrane protein: Q02127
• Total number of polymer chains: 1
• Total formula weight: 42487.79

Authors

Deng, X.,Phillips, M.A. (deposition date: 2014-02-10, release date: 2014-06-04, Last modification date: 2024-02-28)

Primary citation

Deng, X.,Kokkonda, S.,El Mazouni, F.,White, J.,Burrows, J.N.,Kaminsky, W.,Charman, S.A.,Matthews, D.,Rathod, P.K.,Phillips, M.A.
Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors.
J.Med.Chem., 57:5381-5394, 2014

PubMed 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.

PubMed: 24801997
DOI: 10.1021/jm500481t

Experimental method

X-RAY DIFFRACTION (1.23 Å)