3MHU

Crystal structure of dihydroorotate dehydrogenase from Leishmania major in complex with 5-Nitroorotic acid

3MHU の概要

• エントリーDOI: 10.2210/pdb3mhu/pdb
• 関連するPDBエントリー: 3C3N 3GYE
• 分子名称: Dihydroorotate dehydrogenase, FLAVIN MONONUCLEOTIDE, 5-nitro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid, ... (6 entities in total)
• 機能のキーワード: dihydroorotate dehydrogenase, pyrd, oxidoreductase
• 由来する生物種: Leishmania major
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76552.85

構造登録者

Pinheiro, M.P.,Rocha, J.R.,Cheleski, J.,Montanari, C.A.,Nonato, M.C. (登録日: 2010-04-08, 公開日: 2011-02-23, 最終更新日: 2023-09-06)

主引用文献

Cheleski, J.,Rocha, J.R.,Pinheiro, M.P.,Wiggers, H.J.,da Silva, A.B.,Nonato, M.C.,Montanari, C.A.
Novel insights for dihydroorotate dehydrogenase class 1A inhibitors discovery.
Eur.J.Med.Chem., 45:5899-5909, 2010

PubMed Abstract: The enzyme dihydroorotate dehydrogenase (DHODH) has been suggested as a promising target for the design of trypanocidal agents. We report here the discovery of novel inhibitors of Trypanosoma cruzi DHODH identified by a combination of virtual screening and ITC methods. Monitoring of the enzymatic reaction in the presence of selected ligands together with structural information obtained from X-ray crystallography analysis have allowed the identification and validation of a novel site of interaction (S2 site). This has provided important structural insights for the rational design of T. cruzi and Leishmania major DHODH inhibitors. The most potent compound (1) in the investigated series inhibits TcDHODH enzyme with Kiapp value of 19.28 μM and possesses a ligand efficiency of 0.54 kcal mol(-1) per non-H atom. The compounds described in this work are promising hits for further development.

PubMed: 20965617
DOI: 10.1016/j.ejmech.2010.09.055

実験手法

X-RAY DIFFRACTION (1.85 Å)