7E0U

Crystal Structure of Human Indoleamine 2,3-dioxygenagse 1 (hIDO1) Complexed with 6-Bromo-N-(((1S,2S)-2-chlorocyclohexyl)methyl)-1H-indazol-4-amine (39)

7E0U の概要

• エントリーDOI: 10.2210/pdb7e0u/pdb
• 分子名称: Indoleamine 2,3-dioxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, 6-bromanyl-~{N}-[[(1~{S},2~{S})-2-chloranylcyclohexyl]methyl]-1~{H}-indazol-4-amine, ... (4 entities in total)
• 機能のキーワード: indoleamine 2, 3-dioxygenase 1, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 90171.72

構造登録者

Li, G.-B.,Ning, X.-L. (登録日: 2021-01-28, 公開日: 2021-07-21, 最終更新日: 2024-11-13)

主引用文献

Ning, X.L.,Li, Y.Z.,Huo, C.,Deng, J.,Gao, C.,Zhu, K.R.,Wang, M.,Wu, Y.X.,Yu, J.L.,Ren, Y.L.,Luo, Z.Y.,Li, G.,Chen, Y.,Wang, S.Y.,Peng, C.,Yang, L.L.,Wang, Z.Y.,Wu, Y.,Qian, S.,Li, G.B.
X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson's Disease.
J.Med.Chem., 64:8303-8332, 2021

PubMed Abstract: Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson's disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to , which manifested IC values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice. showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar, likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.

PubMed: 34110158
DOI: 10.1021/acs.jmedchem.1c00303

実験手法

X-RAY DIFFRACTION (2.278 Å)