6CJG

Human dihydroorotate dehydrogenase bound to napthyridine inhibitor 46

Summary for 6CJG

• Entry DOI: 10.2210/pdb6cjg/pdb
• Related: 6CJF
• Descriptor: Dihydroorotate dehydrogenase (quinone), mitochondrial, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (8 entities in total)
• Functional Keywords: oxidoreductase, oxidoreductase inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 42200.90

Authors

Petrunak, E.M.,Stuckey, J.A. (deposition date: 2018-02-26, release date: 2018-05-23, Last modification date: 2023-10-04)

Primary citation

Madak, J.T.,Cuthbertson, C.R.,Miyata, Y.,Tamura, S.,Petrunak, E.M.,Stuckey, J.A.,Han, Y.,He, M.,Sun, D.,Showalter, H.D.,Neamati, N.
Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase.
J. Med. Chem., 61:5162-5186, 2018

PubMed Abstract: 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 IC = 9.71 ± 1.4 nM) and 43 (DHODH IC = 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 IC = 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 t = 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.

PubMed: 29727569
DOI: 10.1021/acs.jmedchem.7b01862

Experimental method

X-RAY DIFFRACTION (2.851 Å)