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

doi:10.1038/s41401-019-0246-4

	Discovery and characterization of natural products as novel indoleamine 2,3-dioxygenase 1 inhibitors through high-throughput screening
	Guo, Wei 1,2; Yao, Sheng 3,4; Sun, Pu 1,2; Yang, Tian-biao 4; Tang, Chun-ping 3,4; Zheng, Ming-yue 4; Ye, Yang 3,4,5; Meng, Ling-hua 1,2
刊名	ACTA PHARMACOLOGICA SINICA
	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
DOI	10.1038/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.
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关键词	TUMORAL IMMUNE RESISTANCE ; TRYPTOPHAN 2,3-DIOXYGENASE ; EXPRESSION ; MECHANISM ; IDENTIFICATION ; PURIFICATION ; DERIVATIVES ; ENZYMES ; DESIGN ; LIGAND
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000514159600014
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281511]
专题	中国科学院上海药物研究所
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.