5fi8

Crystal structure of plasmodium falciparum dihydroorotate dehydrogenase bounded with DSM422 (Tetrahydro-2-naphthyl and 2-indanyl triazolopyrimidine)

spinqualitylabelsall models 5fi8, resolution 2.32Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5fi8 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 5Y5, FMN, LDA, 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 persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen. Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity.,Kokkonda S, Deng X, White KL, Coteron JM, Marco M, de Las Heras L, White J, El Mazouni F, Tomchick DR, Manjalanagara K, Rudra KR, Chen G, Morizzi J, Ryan E, Kaminsky W, Leroy D, Martinez-Martinez MS, Jimenez-Diaz MB, Bazaga SF, Angulo-Barturen I, Waterson D, Burrows JN, Matthews D, Charman SA, Phillips MA, Rathod PK J Med Chem. 2016 May 21. PMID:27127993 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydroorotate dehydrogenase

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