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

详细信息    查看全文

• 作者：Jian-Sung Wu ; Shu-Yu Lin ; Fang-Yu Liao ; Wen-Chi Hsiao ; Lung-Chun Lee ; Yi-Hui Peng ; Chia-Ling Hsieh ; Mine-Hsine Wu ; Jen-Shin Song ; Andrew Yueh ; Chun-Hwa Chen ; Shiu-Hwa Yeh ; Chia-Yeh Liu ; Shu-Yi Lin ; Teng-Kuang Yeh ; John T.-A. Hsu ; Chuan Shih ; Shau-Hua Ueng ; Ming-Shiu Hung ; Su-Ying Wu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：October 8, 2015
• 年：2015
• 卷：58
• 期：19
• 页码：7807-7819
• 全文大小：600K
• ISSN：1520-4804

文摘

A structure-based virtual screening strategy, comprising homology modeling, ligand鈥搒upport 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.