基于虚拟筛选发现4-羟基喹啉类新型IDO1抑制剂

张玉萍; 单长宇; 郭海琼; 李宏伟; 欧阳勤; 王远强

doi:10.16016/j.1000-5404.201903051

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基于虚拟筛选发现4-羟基喹啉类新型IDO1抑制剂

药学 | 更新时间：2026-01-09

- 基于虚拟筛选发现4-羟基喹啉类新型IDO1抑制剂
- Discovery of novel 4-hydroxyquinolines as indoleamine 2, 3-dioxygenase 1 inhibitors by virtual screening
- 第三军医大学学报 2019年41卷第16期页码：1601-1610
- 作者机构：
  
  1.400054 重庆，重庆理工大学药学与生物工程学院，药物化学与分子药理学重庆市重点实验室
  2.400038 重庆，陆军军医大学(第三军医大学)药学与检验医学系药物化学教研室
- 作者简介：
  
  [ 欧阳勤, E-mail: ouyangq@tmmu.edu.cn OUYANG Qin, E-mail: ouyangq@tmmu.edu.cn
  [ 王远强，E-mail: wangyqnn@cqut.edu.cn WANG Yuanqiang, E-mail: wangyqnn@cqut.edu.cn
- 基金信息：
- DOI：10.16016/j.1000-5404.201903051
  中图分类号： R319; R914.2; R977.3
- 收稿：2019-03-06，
  
  修回：2019-04-11，
  
  纸质出版：2019-08-30
- 稿件说明：
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张玉萍, 单长宇, 郭海琼, 等. 基于虚拟筛选发现4-羟基喹啉类新型IDO1抑制剂[J]. 第三军医大学学报, 2019,41(16):1601-1610.

Yuping ZHANG, Changyu SHAN, Haiqiong GUO, et al. Discovery of novel 4-hydroxyquinolines as indoleamine 2, 3-dioxygenase 1 inhibitors by virtual screening[J]. Journal of Third Military Medical University, 2019, 41(16): 1601-1610.
张玉萍, 单长宇, 郭海琼, 等. 基于虚拟筛选发现4-羟基喹啉类新型IDO1抑制剂[J]. 第三军医大学学报, 2019,41(16):1601-1610. DOI： 10.16016/j.1000-5404.201903051.

Yuping ZHANG, Changyu SHAN, Haiqiong GUO, et al. Discovery of novel 4-hydroxyquinolines as indoleamine 2, 3-dioxygenase 1 inhibitors by virtual screening[J]. Journal of Third Military Medical University, 2019, 41(16): 1601-1610. DOI： 10.16016/j.1000-5404.201903051.

摘要

目的

采用药效团模型和分子对接方法对ZINC、Chembridge数据库进行虚拟筛选，并通过酶活性测试进行验证，以发现新骨架结构的IDO1抑制剂。

方法

通过分子对接方法靶向IDO1酶活性位点，对ZINC数据库进行虚拟筛选，得到苗头化合物，进行酶活性测试，发现酶活性较好的先导化合物；随后用已进入临床研究的3个IDO1抑制剂构建药效团模型，以此模型对先导化合物类似物进行虚拟筛选，并测定化合物的抑酶活性；通过分子动力学模拟探究化合物与IDO1的结合模式。

结果

通过分子对接方法对超过200万个虚拟化合物进行筛选得到11个先导化合物并测酶活性，其中ZINC91657208抑酶活性较好，IC

约为77.15 μmol/L，活性骨架为4-羟基喹啉。亚结构检索4-羟基喹啉的结构得到31个类似物，利用药效团虚拟筛选出10个化合物，并测酶活性，其中3个4-羟基喹啉类化合物均具有明显的抑酶活性，而Chembridge29374490为酶活性最好的IDO1抑制剂，其IC

约为37.78 μmol/L。经分子动力学模拟平衡后，其骨架原子均方差偏根(root mean square deviation

RMSD)分别为1Å和2.4Å。

结论

从ZINC和Chembridge数据库中发现了新型4-羟基喹啉类IDO1抑制剂。

Abstract

Objective

To discover novel indoleamine 2

3-dioxygenase 1 (IDO1) inhibitors with new scaffold structures by screening ZINC and Chembridge databases using pharmacophore modeling and molecular docking.

Methods

We performed virtual screening of the ZINC database by molecular docking targeting the enzymatic active site of IDO1. The compounds with high scores were selected for enzyme activity test to find the new leads; A pharmacophore model was constructed based on 3 established IDO1 inhibitors that had been tested in clinical trials for virtual screening of the analogues of the lead compounds. The compounds matching the pharmacophore model were selected for inhibitory activity test

and the molecular dynamics was simulated to explore the binding mode of the compounds to IDO1.

Results

With molecular docking

we identified 11 lead compounds from more than 2 million virtual compounds and measured their enzyme activity. Among them

ZINC91657208 with a skeleton of 4-hydroxyquinoline was found to effectively inhibit the enzyme activity of IDO1 with an IC

value of 77.15 μmol/L. Thirty-one analogues were obtained by substructure retrieval with 4-hydroxyquinoline skeleton. Ten compounds were

selected by pharmacophore virtual screening and their inhibitory effect on the enzyme activity of IDO1 was tested. Three of the 10 compounds showed obvious inhibitory activities

and among them Chembridge29374490 had the lowest IC

of 37.78 μmol/L

whose root mean square deviations (RMSD) of the skeleton were 1Å and 2.4Å after equilibrium by molecular dynamics simulation.

Conclusion

We identified new 4-hydroxyquinoline IDO1 inhibitors from ZINC and Chembridge databases.

关键词

Keywords

references

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