6vtn

Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM557

spinqualitylabelsall models 6vtn, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6vtn is a 1 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.25Å Ligands: FMN, ORO, RL7 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 puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds. Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria.,Kokkonda S, Deng X, White KL, El Mazouni F, White J, Shackleford DM, Katneni K, Chiu FCK, Barker H, McLaren J, Crighton E, Chen G, Angulo-Barturen I, Jimenez-Diaz MB, Ferrer S, Huertas-Valentin L, Martinez-Martinez MS, Lafuente-Monasterio MJ, Chittimalla R, Shahi SP, Wittlin S, Waterson D, Burrows JN, Matthews D, Tomchick D, Rathod PK, Palmer MJ, Charman SA, Phillips MA J Med Chem. 2020 Apr 16. doi: 10.1021/acs.jmedchem.0c00311. PMID:32248693 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydroorotate dehydrogenase 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA