2WV8

Complex of human dihydroorotate dehydrogenase with the inhibitor 221290

2WV8 の概要

• エントリーDOI: 10.2210/pdb2wv8/pdb
• 関連するPDBエントリー: 1D3G 1D3H 2B0M 2BXV
• 分子名称: DIHYDROOROTATE DEHYDROGENASE, MITOCHONDRIAL, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (8 entities in total)
• 機能のキーワード: flavoprotein, transmembrane, mitochondrion inner membrane, oxidoreductase, transit peptide, enzyme inhibition, pyrimidine biosynthesis, structure-based drug design, inflamation
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Mitochondrion inner membrane ; Single-pass membrane protein : Q02127
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40954.53

構造登録者

Walse, B.,Svensson, B.,Fritzson, I.,Dahlberg, L.,Wellmar, U.,Al-Karadaghi, S. (登録日: 2009-10-15, 公開日: 2010-08-25, 最終更新日: 2024-05-08)

主引用文献

Fritzson, I.,Svensson, B.,Al-Karadaghi, S.,Walse, B.,Wellmar, U.,Nilsson, U.J.,Da Graca Thrige, D.,Jonsson, S.
Inhibition of Human Dhodh by 4-Hydroxycoumarins, Fenamic Acids, and N-(Alkylcarbonyl)Anthranilic Acids Identified by Structure-Guided Fragment Selection.
Chemmedchem, 5:608-, 2010

PubMed Abstract: A strategy that combines virtual screening and structure-guided selection of fragments was used to identify three unexplored classes of human DHODH inhibitor compounds: 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl)anthranilic acids. Structure-guided selection of fragments targeting the inner subsite of the DHODH ubiquinone binding site made these findings possible with screening of fewer than 300 fragments in a DHODH assay. Fragments from the three inhibitor classes identified were subsequently chemically expanded to target an additional subsite of hydrophobic character. All three classes were found to exhibit distinct structure-activity relationships upon expansion. The novel N-(alkylcarbonyl)anthranilic acid class shows the most promising potency against human DHODH, with IC(50) values in the low nanomolar range. The structure of human DHODH in complex with an inhibitor of this class is presented.

PubMed: 20183850
DOI: 10.1002/CMDC.200900454

実験手法

X-RAY DIFFRACTION (1.9 Å)