6cjg

Human dihydroorotate dehydrogenase bound to napthyridine inhibitor 46

spinqualitylabelsall models 6cjg, resolution 2.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6cjg is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.851Å Ligands: F51, FMN, GOL, ORO, SO4, ZWI Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease PYRD_HUMAN Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:263750; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases. Function PYRD_HUMAN Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. Publication Abstract from PubMed We pursued a structure-guided approach toward the development of improved dihydroorotate dehydrogenase (DHODH) inhibitors with the goal of forming new interactions between DHODH and the brequinar class of inhibitors. Two potential residues, T63 and Y356, suitable for novel H-bonding interactions, were identified in the brequinar-binding pocket. Analogues were designed to maintain the essential pharmacophore and form new electrostatic interactions through strategically positioned H-bond accepting groups. This effort led to the discovery of potent quinoline-based analogues 41 (DHODH IC50 = 9.71 +/- 1.4 nM) and 43 (DHODH IC50 = 26.2 +/- 1.8 nM). A cocrystal structure between 43 and DHODH depicts a novel water mediated H-bond interaction with T63. Additional optimization led to the 1,7-naphthyridine 46 (DHODH IC50 = 28.3 +/- 3.3 nM) that forms a novel H-bond with Y356. Importantly, compound 41 possesses significant oral bioavailability ( F = 56%) and an elimination t1/2 = 2.78 h (PO dosing). In conclusion, the data supports further preclinical studies of our lead compounds toward selection of a candidate for early-stage clinical development. Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase.,Madak JT, Cuthbertson CR, Miyata Y, Tamura S, Petrunak EM, Stuckey JA, Han Y, He M, Sun D, Showalter HD, Neamati N J Med Chem. 2018 May 14. doi: 10.1021/acs.jmedchem.7b01862. PMID:29727569 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