Identification of Substituted Naphthotriazolediones as Novel Tryptophan 2,3-Dioxygenase (TDO) Inhibitors through Structure-Based Virtual Screening.
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.
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Jian-Sung
JS
Wu
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Shu-Yu
SY
Lin
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Fang-Yu
FY
Liao
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Wen-Chi
WC
Hsiao
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Lung-Chun
LC
Lee
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Yi-Hui
YH
Peng
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Chia-Ling
CL
Hsieh
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Mine-Hsine
MH
Wu
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Jen-Shin
JS
Song
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Andrew
A
Yueh
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Chun-Hwa
CH
Chen
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Shiu-Hwa
SH
Yeh
Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Chia-Yeh
CY
Liu
Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Shu-Yi
SY
Lin
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Teng-Kuang
TK
Yeh
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
John T-A
JT
Hsu
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Chuan
C
Shih
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Shau-Hua
SH
Ueng
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Ming-Shiu
MS
Hung
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Su-Ying
SY
Wu
D001665:Binding Sites; D062126:Databases, Chemical; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D004791:Enzyme Inhibitors; D008024:Ligands; D014230:Triazoles; D014366:Tryptophan Oxygenase