期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 11, 页码 5270-5290出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm300260v
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资金
- Ludwig Institute for Cancer Research from the Swiss National Science Foundation [310030130857]
- BioWin
- Health Cluster of Wallonia (Belgium)
- National Institutes of Health (National Center for Research Resources) [2P41RR001081]
- National Institute of General Medical Sciences [9P41GM103311]
Indoleamine 2,3-dioxygenase 1 (IDO1) is an important therapeutic target treatment of diseases such as cancer that involve pathological immune escape. Starting from the scaffold of our previously discovered IDO1 inhibitor 4-phenyl-1,2,3-triazole, we used computational structure-based methods to design more potent ligands. This approach yielded highly efficient low molecular weight inhibitors, the most active being of nanomolar potency both in an enzymatic and in a cellular assay, while showing no cellular toxicity and a high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). A quantitative structure-activity relationship based on the electrostatic ligand-protein interactions in the docked binding modes and on the quantum chemically derived charges of the triazole ring demonstrated a good explanatory power for the observed activities.
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