期刊
FITOTERAPIA
卷 133, 期 -, 页码 137-145出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.fitote.2019.01.005
关键词
Indoleamine 2,3-dioxygenase inhibitor; Indole alkaloids in Picrasma quassioides; Virtual screening; Structure-activity relationship; Enzyme kinetics
资金
- Natural Science Foundation of Shandong Province [ZR2017MH061]
- Key Project for Technology Research and Development of Shandong Province [2018GSF119010]
- Open Project of the State Key Laboratory of Natural Medicine and Traditional Chinese Medicine Injections in Jiangxi Qingfeng Pharmaceutical Co., Ltd., China [QFSKL2018007]
Indoleamine 2,3-dioxygenase (IDO) is one of the important targets for cancer immunotherapy through tryptophan pathway. Recently it has being paid great attention to search potent and safe IDO inhibitor from small-molecule compounds. Picrasma quassioides is a kind of medicinal plant abundant with tryptophan-derived indole alkaloids. By virtual screening and kinetic method for enzymatic analysis, lead compounds with potential DO inhibitory activity were discovered for the first time from PQAs, the natural alkaloids in Picrasma quassioides. The results based on molecular docking analysis and structure-activity relationship (SAR) study demonstrated that coordinating with ferrous ion on the active site of IDO has a great impact on the inhibition potency, and beta-carboline with carboxyl substituted on C-1 is the key pharmacophore for IDO inhibition of PQAs. Enzymatic assay provided further evidence for the effectiveness of beta-carboline-1-carboxylic acid, which displayed as the most potent competitive inhibitor of IDO among these PQAs, and is even more potent than the recognized positive control 1-methyl tryptophan. This natural tryptophan-derived alkaloid thus deserved further deep research as a promising IDO modulator for cancer immunotherapy.
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