6CJG

Human dihydroorotate dehydrogenase bound to napthyridine inhibitor 46

6CJG の概要

• エントリーDOI: 10.2210/pdb6cjg/pdb
• 関連するPDBエントリー: 6CJF
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (8 entities in total)
• 機能のキーワード: oxidoreductase, oxidoreductase inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42200.90

構造登録者

Petrunak, E.M.,Stuckey, J.A. (登録日: 2018-02-26, 公開日: 2018-05-23, 最終更新日: 2023-10-04)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.851 Å)