[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.
点击复制

基于虚拟筛选发现4-羟基喹啉类新型IDO1抑制剂(/HTML )
分享到:

《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.

参考文献/References:

[1]MUNN D H, MELLOR A L. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance[J]. Trends Immunol, 2016, 37(3): 193-207. DOI: 10.1016/j.it.2016.01.002.
[2]LIU M, WANG X, WANG L, et al. Targeting the IDO1 pathway in cancer: from bench to bedside[J]. J Hematol Oncol, 2018, 11(1): 100. DOI: 10.1186/s13045-018-0644-y.
[3]PRENDERGAST G C, MALACHOWSKI W J, MONDAL A, et al. Indoleamine 2, 3-dioxygenase and its therapeutic inhibition in cancer[J]. Int Rev Cell Mol Biol, 2018, 336: 175-203. DOI: 10.1016/bs.ircmb.2017.07.004.
[4]李湘, 樊钱永, 沈舜义. 吲哚胺2, 3-双加氧酶抑制剂及相关抗肿瘤药物开发[J]. 世界临床药物, 2017, 38(7): 483-488. DOI: 10.13683/j.wph.2017.07.012.
LI X, FAN Q Y, SHEN S Y. Indoleamine-2, 3-dioxygenase inhibitor and its related anti-tumor drugs development[J]. World Clin Drugs, 2017, 38(7): 483-488. DOI: 10.13683/j.wph.2017.07.012.
[5]LIU X D, SHIN N, KOBLISH H K, et al. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity[J]. Blood, 2010, 115(17): 3520-3530. DOI: 10.1182/blood-2009-09-246124.
[6]BEATTY G L, O’DWYER P J, CLARK J, et al. First-in-human phase I study of the oral inhibitor of indoleamine 2, 3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies[J]. Clin Cancer Res, 2017, 23(13): 3269-3276. DOI: 10.1158/1078-0432.CCR-16-2272.
[7]SOLIMAN H H, MINTON S E, HAN H S, et al. A phase I study of indoximod in patients with advanced malignancies[J]. Oncotarget, 2016, 7(16): 22928-22938. DOI: 10.18632/oncotarget.8216.
[8]MAUTINO M R, JAIPURI F A, WALDO J, et al. Abstract 491: NLG919, a novel indoleamine-2, 3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy[J]. Cancer Res, 2013, 73(8 Supplement): 491. DOI: 10.1158/1538-7445.am2013-491.
[9]NAYAK-KAPOOR A, HAO Z L, SADEK R, et al. Phase Ia study of the indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors[J]. J Immunother Cancer, 2018, 6(1): 61. DOI: 10.1186/s40425-018-0351-9.
[10]SIU L L, GELMON K, CHU Q, et al. Abstract CT116: BMS-986205, an optimized indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor, is well tolerated with potent pharmacodynamic (PD) activity, alone and in combination with nivolumab (nivo) in advanced cancers in a phase 1/2a trial[J]. Cancer Res, 2017, 77(13 Supplement): CT116. DOI: 10.1158/1538-7445.am2017-ct116.
[11]QIAN S, HE T, WANG W, et al. Discovery and preliminary structure-activity relationship of 1H-indazoles with promising indoleamine-2, 3-dioxygenase 1 (IDO1) inhibition properties[J]. Bioorg Med Chem, 2016, 24(23): 6194-6205. DOI: 10.1016/j.bmc.2016.10.003.
[12]KUMAR S, JALLER D, PATEL B, et al. Structure based development of phenylimidazole-derived inhibitors of indoleamine 2, 3-dioxygenase[J]. J Med Chem, 2008, 51(16): 4968-4977. DOI: 10.1021/jm800512z.
[13]YUE E W, DOUTY B, WAYLAND B, et al. Discovery of potent competitive inhibitors of indoleamine 2, 3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model[J]. J Med Chem, 2009, 52(23): 7364-7367. DOI: 10.1021/jm900518f.
[14]唐光辉, 张娅, 张玉萍, 等. 含磷嘧啶类CDK9抑制剂的分子对接、3D-QSAR和分子动力学模拟[J]. 高等学校化学学报, 2017, 38(11): 2061-2069. DOI: 10.7503/cjcu20170237. 
TANG G H, ZHANG Y, ZHANG Y P, et al. Molecular docking, QSAR and molecular dynamics simulation on phosphorus containing pyrimidines as CDK9 inhibitors[J]. Chem J Chin Univ, 2017, 38(11): 2061-2069. DOI: 10.7503/cjcu20170237.
[15]张洁, 谭初兵, 徐为人, 等. Lipinski五规则的研究进展[J]. 药物评价研究, 2011, 34(6): 451-455. 
ZHANG J, TAN C B, XU W R, et al. Advances in studies on Lipinski’s five rules[J]. Drug Eval Res, 2011, 34(6): 451-455.
[16]MEININGER D, ZALAMEDA L, LIU Y, et al. Purification and kinetic characterization of human indoleamine 2, 3-dioxygenases 1 and 2 (IDO1 and IDO2) and discovery of selective IDO1 inhibitors[J]. Biochim Biophys Acta, 2011, 1814(12): 1947-1954. DOI: 10.1016/j.bbapap.2011.07.023.
[17]汪滢, 唐国荣, 刘澍楠, 等. 结合分子相似性、药效团和分子对接筛选新的HIV-1蛋白酶抑制剂[J]. 生物信息学, 2015, 13(4): 244-250. DOI: 10.3969/j.issn.1672-5565.2015.04.07.
WANG Y, TANG G R, LIU S N, et al. Discovery of new HIV-1 protease inhibitors by integrating molecular similarity, pharmacophore and docking methods[J]. China J Bioinformatics, 2015, 13(4): 244-250. DOI: 10.3969/j.issn.1672-5565.2015.04.07.
[18]李博, 周锐, 何谷, 等. 螺环吲哚类MDM2抑制剂的分子对接、定量构效关系和分子动力学模拟[J]. 化学学报, 2013, 71(10): 1396-1403. DOI: 10.6023/A13040375. 
LI B, ZHOU R, HE G, et al. Molecular docking, QSAR and molecular dynamics simulation on spiro-oxindoles as MDM2 inhibitors[J]. Acta Chimica Sinica, 2013, 71(10): 1396-1403. DOI: 10.6023/A13040375.
[19]MAIER J A, MARTINEZ C, KASAVAJHALA K, et al. Ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB[J]. J Chem Theory Comput, 2015, 11(8): 3696-3713. DOI: 10.1021/acs.jctc.5b00255.
[20]JORGENSEN W L, CHANDRASEKHAR J, MADURA J D, et al. Comparison of simple potential functions for simulating liquid water[J]. J Chem Phys, 1983, 79(2): 926-935. DOI: 10.1063/1.445869.
[21]JAKALIAN A, JACK D B, BAYLY C I. Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation[J]. J Comput Chem, 2002, 23(16): 1623-1641. DOI: 10.1002/jcc.10128.
[22]WANG J M, WOLF R M, CALDWELL J W, et al. Development and testing of a general amber force field[J]. J Comput Chem, 2004, 25(9): 1157-1174. DOI: 10.1002/jcc.20035.
[23]GTZ A W, WILLIAMSON M J, XU D, et al. Routine microsecond molecular dynamics simulations with AMBER on GPUs. 1. generalized born[J]. J Chem Theory Comput, 2012, 8(5): 1542-1555. DOI: 10.1021/ct200909j.
[24]SALOMON-FERRER R, GTZ A W, POOLE D, et al. Routine microsecond molecular dynamics simulations with AMBER on GPUs. 2. explicit solvent particle mesh ewald[J]. J Chem Theory Comput, 2013, 9(9): 3878-3888. DOI: 10.1021/ct400314y.
[25]LONCHARICH R J, BROOKS B R, PASTOR R W. Langevin dynamics of peptides: the frictional dependence of isomerization rates of N-acetylalanyl-N’-methylamide[J]. Biopolymers, 1992, 32(5): 523-535.DOI: 10.1002/bip.360320508.
[26]IZAGUIRRE J A, CATARELLO D P, WOZNIAK J M, et al. Langevin stabilization of molecular dynamics[J]. J Chem Phys, 2001, 114(5): 2090-2098. DOI: 10.1063/1.1332996.
[27]DARDEN T, YORK D, PEDERSEN L. Particle mesh Ewald: An N·log(N) method for Ewald sums in large systems[J]. J Chem Phys, 1993, 98(12): 10089-10092. DOI: 10.1063/1.464397.
[28]ESSMANN U, PERERA L, BERKOWITZ M L, et al. A smooth particle mesh Ewald method[J]. J Chem Phys, 1995, 103(19): 8577-8593. DOI: 10.1063/1.470117.
[29]RYCKAERT J P, CICCOTTI G, BERENDSEN H J C. Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes[J]. J Compt Phys, 1977, 23(3): 327-341. DOI: 10.1016/0021-9991(77)90098-5.
[30]CROSIGNANI S, BINGHAM P, BOTTEMANNE P, et al. Discovery of a novel and selective indoleamine 2, 3-dioxygenase (IDO-1) inhibitor 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2, 5-dione (EOS200271/PF-06840003) and its characterization as a potential clinical candidate[J]. J Med Chem, 2017, 60(23): 9617-9629. DOI: 10.1021/acs.jmedchem.7b00974.
[31]BASRAN J, BOOTH E S, LEE M, et al. Analysis of reaction intermediates in tryptophan 2, 3-dioxygenase: A comparison with indoleamine 2, 3-dioxygenase[J]. Biochemistry, 2016, 55(49): 6743-6750. DOI: 10.1021/acs.biochem.6b01005.
[32]CHENG M F, HUNG M S, SONG J S, et al. Discovery and structure-activity relationships of phenyl benzenesulfonylhydrazides as novel indoleamine 2, 3-dioxygenase inhibitors[J]. Bioorg Med Chem Lett, 2014, 24(15): 3403-3406. DOI: 10.1016/j.bmcl.2014.05.084.
 

更新日期/Last Update: 2019-08-22