Identification of Substituted Naphthotriazolediones as Novel Tryptophan 2,3-Dioxygenase (TDO) Inhibitors through Structure-Based Virtual Screening

被引：50

作者：

Wu, Jian-Sung ^{[1
]}

Lin, Shu-Yu ^{[1
]}

Liao, Fang-Yu ^{[1
]}

Hsiao, Wen-Chi ^{[1
]}

Lee, Lung-Chun ^{[1
]}

Peng, Yi-Hui ^{[1
]}

Hsieh, Chia-Ling ^{[1
]}

Wu, Mine-Hsine ^{[1
]}

Song, Jen-Shin ^{[1
]}

Yueh, Andrew ^{[1
]}

Chen, Chun-Hwa ^{[1
]}

Yeh, Shiu-Hwa ^{[1
]}

Liu, Chia-Yeh ^{[2
]}

Lin, Shu-Yi ^{[2
]}

Yeh, Teng-Kuang ^{[1
]}

Hsu, John T. -A. ^{[1
]}

Shih, Chuan ^{[1
]}

Ueng, Shau-Hua ^{[1
]}

Hung, Ming-Shiu ^{[1
]}

Wu, Su-Ying ^{[1
]}

机构：

[1] Natl Hlth Res Inst, Inst Biotechnol & Pharmaceut Res, Zhunan Town 350, Miaoli County, Taiwan

[2] Natl Hlth Res Inst, Inst Biomed Engn & Nanomed, Zhunan Town 350, Miaoli County, Taiwan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 19期

关键词：

GROWTH-FACTOR RECEPTOR; PROTEIN-TYROSINE PHOSPHATASES; INDOLEAMINE 2,3-DIOXYGENASE; CRYSTAL-STRUCTURE; 3-DIMENSIONAL STRUCTURES; SUBSTRATE RECOGNITION; CATALYTIC MECHANISM; DISCOVERY; ASSAY; LIGAND;

D O I：

10.1021/acs.jmedchem.5b00921

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A structure-based virtual screening strategy, comprising homology modeling, ligand support binding site optimization, virtual screening, and structure clustering analysis, was developed and used to identify novel tryptophan 2,3-dioxygenase (TDO) inhibitors. Compound 1 (IC50 = 711 nM), selected by virtual screening, showed inhibitory activity toward TDO and was subjected to structural modifications and molecular docking studies. This resulted in the identification of a potent TDO selective inhibitor (11e, IC50 = 30 nM), making it a potential compound for further investigation as a cancer therapeutic and other TDO-related targeted therapy.

引用

页码：7807 / 7819

页数：13

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