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Discovery and characterization of natural products as novel indoleamine 2,3-dioxygenase 1 inhibitors through high-throughput screening

文献类型：期刊论文

作者Guo, Wei1,2; Yao, Sheng3,4; Sun, Pu1,2; Yang, Tian-biao4; Tang, Chun-ping3,4; Zheng, Ming-yue4; Ye, Yang3,4,5; Meng, Ling-hua1,2
刊名ACTA PHARMACOLOGICA SINICA
出版日期2020-03-01
卷号41期号:3页码:423-431
关键词indoleamine 2 3-dioxygenase 1 inhibitor natural product library high-throughput fluorescence-based screening
ISSN号1671-4083
DOI10.1038/s41401-019-0246-4
通讯作者Ye, Yang(yye@mail.shcnc.ac.cn) ; Meng, Ling-hua(lhmeng@simm.ac.cn)
英文摘要Indoleamine 2,3-dioxygenase 1 (IDO1) is emerging as a promising therapeutic target for the treatment of malignant tumors characterized by dysregulated tryptophan metabolism. However, the antitumor efficacy of existing small-molecule IDO1 inhibitors is still unsatisfactory, and the underlying mechanism remains largely undefined. To identify novel IDO1 inhibitors, an in-house natural product library of 2000 natural products was screened for inhibitory activity against recombinant human IDO1. High-throughput fluorescence-based screening identified 79 compounds with inhibitory activity > 30% at 20 mu M. Nine natural products were further confirmed to inhibit IDO1 activity by > 30% using Ehrlich's reagent reaction. Compounds 2, 7, and 8 were demonstrated to inhibit IDO1 activity in a cellular context. Compounds 2 and 7 were more potent against IDO1 than TDO2 in the enzymatic assay. The kinetic studies showed that compound 2 exhibited noncompetitive inhibition, whereas compounds 7 and 8 were graphically well matched with uncompetitive inhibition. Compounds 7 and 8 were found to bind to the ferric-IDO1 enzyme. Docking stimulations showed that the naphthalene ring of compound 8 formed "T-shaped" pi-pi interactions with Phe-163 and that the 6-methyl-naphthalene group formed additional hydrophobic interactions with IDO1. Compound 8 was identified as a derivative of tanshinone, and preliminary SAR analysis indicated that tanshinone derivatives may be promising hits for the development of IDO1 inhibitors. This study provides new clues for the discovery of IDO1/TDO2 inhibitors with novel scaffolds.
WOS关键词TUMORAL IMMUNE RESISTANCE ; TRYPTOPHAN 2,3-DIOXYGENASE ; EXPRESSION ; MECHANISM ; IDENTIFICATION ; PURIFICATION ; DERIVATIVES ; ENZYMES ; DESIGN ; LIGAND
资助项目National Natural Science Foundation of China[81773760] ; National Natural Science Foundation of China[81573305] ; National Natural Science Foundation of China[81673327] ; International Partnership Program of the Chinese Academy of Sciences[153631KYSB20160004]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000514159600014
出版者NATURE PUBLISHING GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/281511]  
专题新药研究国家重点实验室
通讯作者Ye, Yang; Meng, Ling-hua
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Nat Prod Chem, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Guo, Wei,Yao, Sheng,Sun, Pu,et al. Discovery and characterization of natural products as novel indoleamine 2,3-dioxygenase 1 inhibitors through high-throughput screening[J]. ACTA PHARMACOLOGICA SINICA,2020,41(3):423-431.
APA Guo, Wei.,Yao, Sheng.,Sun, Pu.,Yang, Tian-biao.,Tang, Chun-ping.,...&Meng, Ling-hua.(2020).Discovery and characterization of natural products as novel indoleamine 2,3-dioxygenase 1 inhibitors through high-throughput screening.ACTA PHARMACOLOGICA SINICA,41(3),423-431.
MLA Guo, Wei,et al."Discovery and characterization of natural products as novel indoleamine 2,3-dioxygenase 1 inhibitors through high-throughput screening".ACTA PHARMACOLOGICA SINICA 41.3(2020):423-431.

入库方式： OAI收割

来源：上海药物研究所

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