基于分子模拟技术探讨豨莶通栓制剂的抗炎作用机制
|
摘要
炎症反应是由外源性和内源性刺激导致机体产生非特异性的抵抗反应。急性缺血性脑梗死发生后,局部缺血区白细胞浸润聚集、黏附。所释放的炎症因子引发损伤级联反应,导致脑组织细胞损害加重,神经功能缺损症状加重,妨碍脑神经元的修复及神经功能的康复。该文以炎症重要通路花生四烯酸代谢途径中的关键靶标为研究对象,构建了s PLA2-ⅡA及COX-2抑制剂的Hiphop药效团模型。结合前期已构建的5-LOX及LTA4H靶标抑制剂药效团模型,初步筛选了豨莶通栓制剂中全部13味中药的成分数据库,选择匹配值大于0. 6成分进行分子对接研究,将对接CDOCKER打分值大于原配体打分值的80%的成分作为靶标的潜在活性抑制剂。综合考虑药效团匹配值、分子对接打分值和成分与靶标之间的相互作用,选择了1个川芎成分及1个红花成分作为s PLA2-ⅡA的潜在抑制剂; 2个川芎成分、2个三七成分、1个红花成分、1个当归成分、1个豨莶草成分作为COX-2的潜在抑制剂; 2个秦艽成分、1个红花成分、1个豨莶草成分、1个三七成分以及1个当归成分作为5-LOX的潜在抑制剂; 2个秦艽成分、2个川芎成分、2个红花成分作为LTA4H的潜在抑制剂。该研究快速高效筛选了豨莶通栓制剂中的s PLA2-ⅡA,COX-2,5-LOX,LTA4H靶标的潜在抑制剂,阐释了豨莶通栓制剂同时作用于花生四烯酸代谢途径中的LOX通路以及COX通路从而发挥治疗缺血性脑卒中引起的炎症反应的机制。
Inflammatory response is caused by exogenous and endogenous stimuli,resulting in a non-specific resistance reaction.After acute ischemic cerebral infarction,inflammatory factors gather and adhere in the ischemic area of leukocyte infiltration,and the released inflammatory factors causes the injury cascade,aggravate the brain tissue damage and the symptoms of neurological deficits,and hinder the repair of brain neurons and the recovery of nerve function. In this paper,the key targets in the arachidonic acid metabolic pathway were studied. The Hiphop pharmacophore model of s PLA2-ⅡA and COX-2 inhibitors was built. According tothe two previously constructed 5-LOX and LTA4 H target inhibitors,the pharmacophore model was used to initially screen out the composition database of all of 13 traditional Chinese medicines in Xixian Tongshuan Preparation. The molecular matching study was carried out by selecting the matching value greater than 0. 6,and the component with the CDOCKER score greater than 80% of the original ligand score was used as the potential active inhibitor of the target. Considering the pharmacophore matching value,the molecular docking score and the interaction between the components and the target,one Chuanxiong component and one safflower component were selected as potential inhibitors of s PLA2-ⅡA; two Chuanxiong components,two Panax notoginseng,one safflower component,one angelica component,one valerian component were taken as a potential inhibitor of COX-2; two Gentiana components,one safflower component,one valerian component,one P. notoginseng component and one Angelica component were taken as potential inhibitors of 5-LOX; and two Gentiana components,two Chuanxiong components,and two safflower components were taken as potential inhibitors of LTA4 H. This study screened out the potential inhibitors of the four targets in a high-efficiency and low-cost manner,and explained that Xixian Tongshuan Preparation showed an effect in the treatment of inflammatory responses caused by ischemic stroke by acting both LOX pathway and COX pathway in the metabolic pathway.
Inflammatory response is caused by exogenous and endogenous stimuli,resulting in a non-specific resistance reaction.After acute ischemic cerebral infarction,inflammatory factors gather and adhere in the ischemic area of leukocyte infiltration,and the released inflammatory factors causes the injury cascade,aggravate the brain tissue damage and the symptoms of neurological deficits,and hinder the repair of brain neurons and the recovery of nerve function. In this paper,the key targets in the arachidonic acid metabolic pathway were studied. The Hiphop pharmacophore model of s PLA2-ⅡA and COX-2 inhibitors was built. According tothe two previously constructed 5-LOX and LTA4 H target inhibitors,the pharmacophore model was used to initially screen out the composition database of all of 13 traditional Chinese medicines in Xixian Tongshuan Preparation. The molecular matching study was carried out by selecting the matching value greater than 0. 6,and the component with the CDOCKER score greater than 80% of the original ligand score was used as the potential active inhibitor of the target. Considering the pharmacophore matching value,the molecular docking score and the interaction between the components and the target,one Chuanxiong component and one safflower component were selected as potential inhibitors of s PLA2-ⅡA; two Chuanxiong components,two Panax notoginseng,one safflower component,one angelica component,one valerian component were taken as a potential inhibitor of COX-2; two Gentiana components,one safflower component,one valerian component,one P. notoginseng component and one Angelica component were taken as potential inhibitors of 5-LOX; and two Gentiana components,two Chuanxiong components,and two safflower components were taken as potential inhibitors of LTA4 H. This study screened out the potential inhibitors of the four targets in a high-efficiency and low-cost manner,and explained that Xixian Tongshuan Preparation showed an effect in the treatment of inflammatory responses caused by ischemic stroke by acting both LOX pathway and COX pathway in the metabolic pathway.
引文
[1]国家卫生健康委脑卒中防治工程委员会.中国脑卒中防治指导规范脑卒中筛查与防治技术规范[M].北京:人民卫生出版社,2018:4.
[2]陈灏珠,林果为,王吉耀.实用内科学[M].14版.北京:人民卫生出版社,2013:2721.
[3]郑泽荣,肖波,覃伟钊.芪参益气滴丸对急性缺血性脑梗死病人炎症反应的影响[J].中西医结合心脑血管病杂志,2018,16(15):2128.
[4]麦鸿成,陈丹霞,徐炳东,等.炎症反应与缺血性脑卒中后出血转换[J].海南医学,2017,28(22):3705.
[5]陈梅,王立新.中药联合干细胞疗法治疗缺血性脑卒中的研究进展[J].中国实验方剂学杂志,2017,23(19):218.
[6] Schaloske R H,Dennis E A. The phospholipase A2 superfamily and its group numbering system[J]. Biochim Biophys Acta,2006,1761(11):1246.
[7] Shimizu T. Lipid mediators in health and disease:enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation[J]. Pharmacol Toxicol,2009,49(49):123.
[8] Divchev D,Schieffer B. The secretory phospholipase A2 groupⅡA:a missing link between inflammation,activated renin-angiotensin system,and atherogenesis?[J]. Vasc Health Risk Manag,2008,4(3):597.
[9] Sharma J N,Mohammed L A. The role of leukotrienes in the pathophysiology of inflammatory disorders:is there a case for revisiting leukotrienes as therapeutic targets?[J]. Inflammopharmacology,2006,14(2):10.
[10] Jiang X,Zhou L D,Meng H,et al. Activation and inhibition of leukotriene A 4,hydrolase aminopeptidase activity by diphenyl ether and derivatives[J]. Bioorg Med Chem Lett,2008,18(24):6549.
[11] Tak P P,Bresnihan B. The pathogenesis and prevention of joint damage in rheumatoid arthritis:advances from synovial biopsy and tissue analysis[J]. Arthritis Rheum,2000,43(12):2619.
[12] Wedmore C V,Williams T J. Control of vascular permeability by plymorphonuelear leukoeytes in inflammation[J]. Nature,1981,289:646.
[13] Bingham C O. The pathogenesis of rheumatoid arthritis:pivotal cytokines involved in bone degradation and inflammation[J].J Rheumatol,2002,65(5):3.
[14]杨尧,周瑶,郁彭,等.白三烯A4水解酶及其抑制药研究进展[J].医药导报,2015,34(2):225.
[15]孙晨捷,王营忠.环氧化酶-2与ACS的关系研究进展[J].世界最新医学信息文摘,2017,17(86):69.
[16] Yu L,Yang B,Wang J,et al. Time course change of COX2-PGI2/TXA2 following global cerebral ischemia reperfusion injury in rat hippocampus[J]. Behav Brain Funct,2014,10(1):42.
[17]刘莹,陈政,尚尔昌,等.花生四烯酸代谢网络研究:从关键酶的单靶标抑制剂到多靶标抑制剂[J].药学学报,2009,44(3):231.
[18]蒋世云,魏娜,傅凤鸣.环氧化酶-2/5-脂氧合酶双效抑制剂的抗炎研究进展[J].昆明理工大学学报:自然科学版,2017,42(4):73.
[19] Wang G,Zhao X,Ning L I,et al. Antiatherosclerosis induced by ligustrazine against LPS through arachidonicacid signaling pathway[J]. J Med Plants Res,2013,28(3):563.
[20]杨晔.抗病毒相关药效团的构建及评价方法研究[D].北京:北京中医药大学,2010.
[21] Fabrizio G,Daniel P,Ingemar S,et al. Discovery of AZD2716:a novel secreted phospholipaseA2(s PLA2)inhibitor for the treatment of coronary artery disease[J]. ACS Med Chem Lett,2016,7(10):884.
[22] Team E W. The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2:the second clinical candidate having a shorter and favorable human half-life[J]. Bioorg Med Chem Lett,2010,20(23):7159.
[23] Xiao Q,Dong N,Yao X,et al. Bufexamac ameliorates LPS-induced acute lung injury in mice by targeting LTA4H[J]. Sci Rep,2016,6:25298.
[24]严辉,陈佩东,丁安伟.蒲黄的炮制及其化学成分、药理作用的研究进展[J].江苏中医药,2005,26(1):59.
[25]蒋春丽,白玫,杨春辉,等.呫吨酮类化合物的药理作用研究进展[J].现代药物与临床,2013,28(3):452.
[2]陈灏珠,林果为,王吉耀.实用内科学[M].14版.北京:人民卫生出版社,2013:2721.
[3]郑泽荣,肖波,覃伟钊.芪参益气滴丸对急性缺血性脑梗死病人炎症反应的影响[J].中西医结合心脑血管病杂志,2018,16(15):2128.
[4]麦鸿成,陈丹霞,徐炳东,等.炎症反应与缺血性脑卒中后出血转换[J].海南医学,2017,28(22):3705.
[5]陈梅,王立新.中药联合干细胞疗法治疗缺血性脑卒中的研究进展[J].中国实验方剂学杂志,2017,23(19):218.
[6] Schaloske R H,Dennis E A. The phospholipase A2 superfamily and its group numbering system[J]. Biochim Biophys Acta,2006,1761(11):1246.
[7] Shimizu T. Lipid mediators in health and disease:enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation[J]. Pharmacol Toxicol,2009,49(49):123.
[8] Divchev D,Schieffer B. The secretory phospholipase A2 groupⅡA:a missing link between inflammation,activated renin-angiotensin system,and atherogenesis?[J]. Vasc Health Risk Manag,2008,4(3):597.
[9] Sharma J N,Mohammed L A. The role of leukotrienes in the pathophysiology of inflammatory disorders:is there a case for revisiting leukotrienes as therapeutic targets?[J]. Inflammopharmacology,2006,14(2):10.
[10] Jiang X,Zhou L D,Meng H,et al. Activation and inhibition of leukotriene A 4,hydrolase aminopeptidase activity by diphenyl ether and derivatives[J]. Bioorg Med Chem Lett,2008,18(24):6549.
[11] Tak P P,Bresnihan B. The pathogenesis and prevention of joint damage in rheumatoid arthritis:advances from synovial biopsy and tissue analysis[J]. Arthritis Rheum,2000,43(12):2619.
[12] Wedmore C V,Williams T J. Control of vascular permeability by plymorphonuelear leukoeytes in inflammation[J]. Nature,1981,289:646.
[13] Bingham C O. The pathogenesis of rheumatoid arthritis:pivotal cytokines involved in bone degradation and inflammation[J].J Rheumatol,2002,65(5):3.
[14]杨尧,周瑶,郁彭,等.白三烯A4水解酶及其抑制药研究进展[J].医药导报,2015,34(2):225.
[15]孙晨捷,王营忠.环氧化酶-2与ACS的关系研究进展[J].世界最新医学信息文摘,2017,17(86):69.
[16] Yu L,Yang B,Wang J,et al. Time course change of COX2-PGI2/TXA2 following global cerebral ischemia reperfusion injury in rat hippocampus[J]. Behav Brain Funct,2014,10(1):42.
[17]刘莹,陈政,尚尔昌,等.花生四烯酸代谢网络研究:从关键酶的单靶标抑制剂到多靶标抑制剂[J].药学学报,2009,44(3):231.
[18]蒋世云,魏娜,傅凤鸣.环氧化酶-2/5-脂氧合酶双效抑制剂的抗炎研究进展[J].昆明理工大学学报:自然科学版,2017,42(4):73.
[19] Wang G,Zhao X,Ning L I,et al. Antiatherosclerosis induced by ligustrazine against LPS through arachidonicacid signaling pathway[J]. J Med Plants Res,2013,28(3):563.
[20]杨晔.抗病毒相关药效团的构建及评价方法研究[D].北京:北京中医药大学,2010.
[21] Fabrizio G,Daniel P,Ingemar S,et al. Discovery of AZD2716:a novel secreted phospholipaseA2(s PLA2)inhibitor for the treatment of coronary artery disease[J]. ACS Med Chem Lett,2016,7(10):884.
[22] Team E W. The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2:the second clinical candidate having a shorter and favorable human half-life[J]. Bioorg Med Chem Lett,2010,20(23):7159.
[23] Xiao Q,Dong N,Yao X,et al. Bufexamac ameliorates LPS-induced acute lung injury in mice by targeting LTA4H[J]. Sci Rep,2016,6:25298.
[24]严辉,陈佩东,丁安伟.蒲黄的炮制及其化学成分、药理作用的研究进展[J].江苏中医药,2005,26(1):59.
[25]蒋春丽,白玫,杨春辉,等.呫吨酮类化合物的药理作用研究进展[J].现代药物与临床,2013,28(3):452.