基于网络药理学研究大川芎方治疗偏头痛的作用机制
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摘要
目的研究大川芎方治疗偏头痛的分子作用机制。方法结合文献挖掘、分子对接和网络分析研究大川芎方中化合物群与偏头痛相关靶蛋白的相互作用。结果分子对接发现大川芎中有38个活性成分,且大部分具有较好的口服生物利用度和良好的脑内暴露量,进一步网络分析发现senkyunolide M,riligustilide,levistolide A,chuanxiongterpene等16个化合物为其主要活性成分,可通过与CGRP、p38、TNF-α、iGluR5、NOS等18个靶蛋白作用,抑制神经源性炎症和神经递质的产生,降低源自三叉神经的感受器对伤害性信息的超敏化,并对抗皮层扩布性抑制,从而发挥治疗偏头痛的作用。结论通过网络分析明确了大川芎方治疗偏头痛的分子作用机制,诠释了其科学内涵,有助于推动后续相应制剂的药效物质基础研究和分子机制实验研究。
OBJECTIVE To understand the mechanism of Dachuanxiong Fang on migraine.METHODS Data mining,Molecular docking and Network Analysis were employed to investigate the active compounds and key target protein.RESULTS38 active hits were identified by virtual screening,of which,most compounds had good oral bioavailability and might be optimal CNS exposure.Among them,16molecules(senkyunolide M,levistolide A,chuanxiongterpene,riligustilide,etc.)could significantly contribute to alleviate migraine.And they could target 18protein(such as CGRP,p38,TNF-α,iGluR5,NOS)to inhibit neurogenic inflammation and neutrotransmitters,to reduce the sensitive of nociceptors originated in the trigeminal ganglion,and to combat the genesis and propagation of cortical spreading depression.CONCLUSION It was illustrated the molecular mechanism and the key active compounds of Dachuanxiong Fang,which was helpful for wet experiments to explore targets and active compounds.
OBJECTIVE To understand the mechanism of Dachuanxiong Fang on migraine.METHODS Data mining,Molecular docking and Network Analysis were employed to investigate the active compounds and key target protein.RESULTS38 active hits were identified by virtual screening,of which,most compounds had good oral bioavailability and might be optimal CNS exposure.Among them,16molecules(senkyunolide M,levistolide A,chuanxiongterpene,riligustilide,etc.)could significantly contribute to alleviate migraine.And they could target 18protein(such as CGRP,p38,TNF-α,iGluR5,NOS)to inhibit neurogenic inflammation and neutrotransmitters,to reduce the sensitive of nociceptors originated in the trigeminal ganglion,and to combat the genesis and propagation of cortical spreading depression.CONCLUSION It was illustrated the molecular mechanism and the key active compounds of Dachuanxiong Fang,which was helpful for wet experiments to explore targets and active compounds.
引文
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[26]BARABASI A-L.Scale-Free Networks:A Decade and Beyond[J].Science,2009,325(5939):412-413.
[27]HERT J,KEISER MJ,IRWIN JJ,et al.Quantifying the relationships among drug classes[J].J Chem Inf Model,2008,48(4):755-765.
[28]ANTONOVA M,WIENECKE T,OLESEN J,et al.Prostaglandins in migraine:update[J].Curr Opin Neurol,2013,26(3):269-275.
[29]ZHANG XC,KAINZ V,BURSTEIN R,et al.Tumor necrosis factor-alpha induces sensitization of meningeal nociceptors mediated via local COX and p38MAP kinase actions[J].Pain,2011,152(1):140-149.
[30]OLESEN J.The role of nitric oxide(NO)in migraine,tension-type headache and cluster headache[J].Pharm Ther,2008,120(2):157-171.
[31]GOADSBY PJ,CHARBIT AR,ANDREOU AP,et al.Neurobiology of migraine[J].Neuroscience,2009,161(2):327-341.
[32]周明眉,杨奎,王一涛.大川芎方对硝酸甘油偏头痛模型大鼠硬脑膜血管及三叉神经核NOS、SP和CGRP受体的影响[J].中药药理与临床,2009,25(6):9-10.ZHOU MM,YANG K,WANG YT.Effects of Dachuanxiong Fang on the express of NOS,SP,CGRP in the dural vessels and Trigeminal nerve nuclei of rats with nitroglycerin-induced migraine model[J].Pharm Clin Chin Mater Med,2009,25(6):9-10.
[33]DEL SOL A,BALLING R,HOOD L,et al.Diseases as network perturbations[J].Curr Opin Biotechnol,2010,21(4):566-571.
[34]LU JJ,PAN W,HU YJ,et al.Multi-target drugs:The trend of drug research and development[J].PLoS One,2012,7(6):e40262.
[35]CSERMELY P,AGOSTON V,PONGOR S.The efficiency of multi-target drugs:the network approach might help drug design[J].Trends Pharmacol Sci,2005,26(4):178-182.
[36]HOPKINS AL.Network pharmacology:the next paradigm in drug discovery[J].Nat Chem Biol,2008,4(11):682-690.
[37]LI S,ZHANG B.Traditional Chinese medicine network pharmacology:theory,methodology and application[J].Chin J Natl Med,2013,11(02):110-120.
[38]GERTSCH J.Botanical drugs,synergy,and network pharmacology:forth and back to intelligent mixtures[J].Planta Med,2011,77(11):1086-1098.
[39]NAGY AJ,RAPOPORT AM.Update on future headache treatments[J].Neurol Sci,2013,34Suppl 1:S101-108.
[40]VOLLBRACHT S,RAPOPORT AM.New treatments for headache[J].Neurol Sci,2014,35Suppl 1:89-97.
[41]BLUMENFELD A,GENNINGS C,CADY R.Pharmacological synergy:the next frontier on therapeutic advancement for migraine[J].Headache,2012,52(4):636-647.
[42]GONZALEZ-HERNANDEZ A,CONDES-LARA M.The multitarget drug approach in migraine treatment:the new challenge to conquer[J].Headache,2014,54(1):197-199.
[2]GALLETTI F,CUPINI LM,CORBELLI I,et al.Pathophysiological basis of migraine prophylaxis[J].Prog Neurobiol,2009,89(2):176-192.
[3]MOSKOWITZ MA.Pathophysiology of headache-past and present[J].Headache,2007,47Suppl 1:S58-63.
[4]HOPKINS AL.Network pharmacology[J].Nat Biotech,2007,25(10):1110-1111.
[5]BERGER SI,IYENGAR R.Network analyses in systems pharmacology[J].Bioinform,2009,25(19):2466-2472.
[6]HASAN S,BONDE BK,BUCHAN NS,et al.Network analysis has diverse roles in drug discovery[J].Drug Dis Today,2012,17(15-16):869-874.
[7]LI J,LU C,JIANG M,et al.Traditional chinese medicinebased network pharmacology could lead to new multicompound drug discovery[J].Evid Based Complement Alternat Med,2012,2012:149762.
[8]LIANG X,LI H,LI S.A novel network pharmacology approach to analyse traditional herbal formulae:the Liu-Wei-DiHuang pill as a case study[J].Mol Biosyst,2014,10(5):1014-1022.
[9]PEROUTKA SJ.Neurogenic inflammation and migraine:implications for the therapeutics[J].Mol Interv,2005,5(5):304-311.
[10]CHAN K,MAASSENVANDENBRINK A.Glutamate receptor antagonists in the management of migraine[J].Drugs,2014,74(11):1165-1176.
[11]GUPTA S,VILLALON CM.The relevance of preclinical research models for the development of antimigraine drugs:Focus on 5-HT1B/1D and CGRP receptors[J].Pharm Ther,2010,128(1):170-190.
[12]WANG YH,LIANG S,XU DS,et al.Effect and mechanism of senkyunolide I as an anti-migraine compound from Ligusticum chuanxiong[J].J Pharm Pharmacol,2011,63(2):261-266.
[13]ZHU MD,ZHAO LX,WANG XT,et al.Ligustilide inhibits microglia-mediated proinflammatory cytokines production and inflammatory pain[J].Brain Res Bull,2014,109:54-60.
[14]JUAREZ-REYES K,ANGELES-LOPEZ GE,RIVEROCRUZ I,et al.Antinociceptive activity of Ligusticum porteri preparations and compounds[J].Pharm Biol,2014,52(1):14-20.
[15]MEANWELL NA.Improving Drug Candidates by Design:A Focus on Physicochemical Properties As a Means of Improving Compound Disposition and Safety[J].Chem Res Toxicol,2011,24(9):1420-1456.
[16]RANKOVIC Z.CNS Drug Design:Balancing physicochemical properties for optimal brain exposure[J].J Med Chem,2015,58(6):2584-2608.
[17]王强,沈岚,房鑫,等.大川芎方沿体外-血浆-脑脊液-脑组织的移行成分研究[J].中成药,2013,35(11):2364-2371.WANG Q,SHEN L,FANG X,et al.Shift of effective ingredients of Dachuanxiong Decoction along in vitro-plasma-cerebrospinal fluid-brain tissue[J].Chin Tradit Pat Med,2013,35(11):2364-2371.
[18]沈岚,林晓,洪燕龙,等.大川芎方效应组分血浆及脑脊液HPLC特征指纹图谱研究[J].中国中药杂志,2012,37(13):2017-2021.SHEN L,LIN X,HONG YL,et al.Study on HPLC characteristic fingerprint of active components of Dachuanxiong Fang in plasma and cerebrospinal fluid[J].China J Chin Mater Med,2012,37(13):2017-2021.
[19]倪书茂,钱大玮,段金廒,等.大川芎方中藁本内酯及天麻素在家兔血浆中的代谢物研究[J].中成药,2010,32(7):1115-1120.NI SM,QIAN DW,DUAN JA,et al.Metablites of ligustilide and gastrodin from Dachuanxiong Decoction in rabbit plasma[J].Chin Tradit Pat Med,2010,32(7):1115-1120.
[20]BROHEE S,FAUST K,LIMA-MENDEZ G,et al.Network Analysis Tools:from biological networks to clusters and pathways[J].Nat Prot,2008,3(10):1616-1629.
[21]BAUER-MEHREN A,BUNDSCHUS M,RAUTSCHKA M,et al.Gene-disease network analysis reveals functional modules in mendelian,complex and environmental diseases[J].PLoS One,2011,6(6):e20284.
[22]KUSHWAHA SK,SHAKYA M.Protein interaction network analysis:Approach for potential drug target identification in Mycobacterium tuberculosis[J].J Theor Biol,2010,262(2):284-294.
[23]IORIO F,BOSOTTI R,SCACHERI E,et al.Discovery of drug mode of action and drug repositioning from transcriptional responses[J].Proc Natl Acad Sci USA,2010,107(33):14621-14626.
[24]HWANG WC,ZHANG A,RAMANATHAN M.Identification of information flow-modulating drug targets:a novel bridging paradigm for drug discovery[J].Clin Pharmacol Ther,2008,84(5):563-572.
[25]TSUCHIYA M,SELVARAJOO K,PIRAS V,et al.Local and global responses in complex gene regulation networks[J].Physica A,2009,388(8):1738-1746.
[26]BARABASI A-L.Scale-Free Networks:A Decade and Beyond[J].Science,2009,325(5939):412-413.
[27]HERT J,KEISER MJ,IRWIN JJ,et al.Quantifying the relationships among drug classes[J].J Chem Inf Model,2008,48(4):755-765.
[28]ANTONOVA M,WIENECKE T,OLESEN J,et al.Prostaglandins in migraine:update[J].Curr Opin Neurol,2013,26(3):269-275.
[29]ZHANG XC,KAINZ V,BURSTEIN R,et al.Tumor necrosis factor-alpha induces sensitization of meningeal nociceptors mediated via local COX and p38MAP kinase actions[J].Pain,2011,152(1):140-149.
[30]OLESEN J.The role of nitric oxide(NO)in migraine,tension-type headache and cluster headache[J].Pharm Ther,2008,120(2):157-171.
[31]GOADSBY PJ,CHARBIT AR,ANDREOU AP,et al.Neurobiology of migraine[J].Neuroscience,2009,161(2):327-341.
[32]周明眉,杨奎,王一涛.大川芎方对硝酸甘油偏头痛模型大鼠硬脑膜血管及三叉神经核NOS、SP和CGRP受体的影响[J].中药药理与临床,2009,25(6):9-10.ZHOU MM,YANG K,WANG YT.Effects of Dachuanxiong Fang on the express of NOS,SP,CGRP in the dural vessels and Trigeminal nerve nuclei of rats with nitroglycerin-induced migraine model[J].Pharm Clin Chin Mater Med,2009,25(6):9-10.
[33]DEL SOL A,BALLING R,HOOD L,et al.Diseases as network perturbations[J].Curr Opin Biotechnol,2010,21(4):566-571.
[34]LU JJ,PAN W,HU YJ,et al.Multi-target drugs:The trend of drug research and development[J].PLoS One,2012,7(6):e40262.
[35]CSERMELY P,AGOSTON V,PONGOR S.The efficiency of multi-target drugs:the network approach might help drug design[J].Trends Pharmacol Sci,2005,26(4):178-182.
[36]HOPKINS AL.Network pharmacology:the next paradigm in drug discovery[J].Nat Chem Biol,2008,4(11):682-690.
[37]LI S,ZHANG B.Traditional Chinese medicine network pharmacology:theory,methodology and application[J].Chin J Natl Med,2013,11(02):110-120.
[38]GERTSCH J.Botanical drugs,synergy,and network pharmacology:forth and back to intelligent mixtures[J].Planta Med,2011,77(11):1086-1098.
[39]NAGY AJ,RAPOPORT AM.Update on future headache treatments[J].Neurol Sci,2013,34Suppl 1:S101-108.
[40]VOLLBRACHT S,RAPOPORT AM.New treatments for headache[J].Neurol Sci,2014,35Suppl 1:89-97.
[41]BLUMENFELD A,GENNINGS C,CADY R.Pharmacological synergy:the next frontier on therapeutic advancement for migraine[J].Headache,2012,52(4):636-647.
[42]GONZALEZ-HERNANDEZ A,CONDES-LARA M.The multitarget drug approach in migraine treatment:the new challenge to conquer[J].Headache,2014,54(1):197-199.