[1]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):1601-1606.
 ZHANG Yuping,SHAN Changyu,GUO Haiqiong,et al.Discovery of novel 4-hydroxyquinolines as indoleamine 2,3-dioxygenase 1 inhibitors by virtual screening[J].J Third Mil Med Univ,2019,41(16):1601-1606.
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基于虚拟筛选发现4-羟基喹啉类新型IDO1抑制剂(/HTML )
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《第三军医大学学报》[ISSN:1000-5404/CN:51-1095/R]

卷:
41卷
期数:
2019年第16期
页码:
1601-1606
栏目:
药学
出版日期:
2019-08-30

文章信息/Info

Title:
Discovery of novel 4-hydroxyquinolines as indoleamine 2,3-dioxygenase 1 inhibitors by virtual screening
作者:
张玉萍单长宇郭海琼李宏伟欧阳勤王远强
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;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
Author(s):
ZHANG Yuping SHAN Changyu GUO Haiqiong LI Hongwei OUYANG Qin WANG Yuanqiang

Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054; Department of Medicinal Chemistry, Faculty of Pharmacy & Laboratory Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China

关键词:
IDO1抑制剂分子对接IDO1酶活性药效团筛选分子动力学模拟
Keywords:
indoleamine 23-dioxygenase 1 inhibitors molecular docking pharmacophore modeling enzyme activity molecular dynamics simulation
分类号:
R319;R914.2;R977.3
文献标志码:
A
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,IC50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IC50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1和2.4。结论从ZINC和Chembridge数据库中发现了

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. MethodsWe 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. ResultsWith 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 IC50 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 IC50 of 37.78 μmol/L, whose root mean square deviations (RMSD) of the skeleton were 1 and 2.4 after equilibrium by molecular dynamics simulation. ConclusionWe identified new 4-hydroxyquinoline IDO1 inhibitors from ZINC and Chembridge databases.

更新日期/Last Update: 2019-08-22