6gjg | pdb_00006gjg

Plasmodium falciparum dihydroorotate dehydrogenase DHODH in complex with 3,6-dimethyl-N-(4-(trifluoromethyl)phenyl)-(1,2)oxazolo(5,4-d)pyrimidin-4-amine

spinqualitylabelsall models 6gjg, resolution 1.99Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6gjg is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: F1T, FMN, ORO Activity: Dihydroorotate dehydrogenase (quinone), with EC number 1.3.5.2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [PYRD_PLAF7] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. Publication Abstract from PubMed Malaria kills nearly 0.5 million people yearly and impacts the lives of those living in over 90 countries where it is endemic. The current treatment programs are threatened by increasing drug resistance. Dihydroorotate dehydrogenase (DHODH) is now clinically validated as a target for antimalarial drug discovery as a triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. We discovered a related isoxazolopyrimidine series in a phenotypic screen, later determining that it targeted DHODH. To determine if the isoxazolopyrimidines could yield a drug candidate, we initiated hit-to-lead medicinal chemistry. Several potent analogues were identified, including a compound that showed in vivo antimalarial activity. The isoxazolopyrimidines were more rapidly metabolized than their triazolopyrimidine counterparts, and the pharmacokinetic data were not consistent with the goal of a single-dose treatment for malaria. Isoxazolopyrimidine-Based Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Antimalarial Activity.,Kokkonda S, El Mazouni F, White KL, White J, Shackleford DM, Lafuente-Monasterio MJ, Rowland P, Manjalanagara K, Joseph JT, Garcia-Perez A, Fernandez J, Gamo FJ, Waterson D, Burrows JN, Palmer MJ, Charman SA, Rathod PK, Phillips MA ACS Omega. 2018 Aug 31;3(8):9227-9240. doi: 10.1021/acsomega.8b01573. Epub 2018, Aug 15. PMID:30197997 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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