基于分子对接探讨红芪中小分子拮抗肿瘤坏死因子受体1的可能性
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摘要
目的:基于分子对接的方法研究拮抗肿瘤坏死因子受体1(TNFR1)的红芪小分子化合物。方法:从相关中药化学成分化合物库下载红芪小分子化合物结构,进行结构优化,获得红芪成分化合物库;确定炎症靶点TNFR1三维结构(PDB ID:1TNR),进行加氢、去水等处理,根据文献确定结合口袋残基;根据确定的靶点结构和结合口袋,将成分化合物库与靶点进行柔性分子对接,获得打分值(Glide Score);基于分子对接结果,选择Glide Score前9个小分子化合物为候选成分,在此基础上进行类药性分析,即符合氢键受体数、氢键供体数量、分子量、可旋转键的数量、脂水分配系数的数值范围的小分子化合物;最后根据药代动力学参数及成分-靶点对接的复合物结构进行结合模式分析。结果:确定TNFR1药物结合口袋的残基组成为谷氨酸109(Glu109),赖氨酸35(Lys35),丙氨酸62(Ala62),丝氨酸74(Ser74),赖氨酸75(Lys75),半胱氨酸76(Cys76),精氨酸77(Arg77),谷氨酸82(Gln82),苏氨酸89(Thr89),天冬氨酸91(Asp91),精氨酸92(Arg92),天冬氨酸93(Asp93),苏氨酸94(Thr94),缬氨酸95(Val95),半胱氨酸96(Cys96),精氨酸104(Arg104),酪氨酸106(Tyr106),天冬酰胺110(Asn110),亮氨酸111(Leu111),苯丙氨酸112(Phe112),谷氨酸131(Glu131),赖氨酸132(Lys132);检索得到红芪43个小分子化合物;以对接打分等综合筛选出槲皮素、异甘草素、柚皮素、毛蕊异黄酮及甘草素5个红芪小分子化合物。结论:红芪抗炎的有效物质基础槲皮素、异甘草素、柚皮素、毛蕊异黄酮及甘草素具有成为TNFR1拮抗剂的较大可能性。
Objective:To study the effect of small molecule compounds of Hedysari Radix in ntagonizing tumor necrosis factor receptor type 1(TNFR1) based on molecular docking.Method:The structure of small molecular compound of Hedysari Radix was downloaded from the chemical composition compound library of traditional Chinese medicine,and then optimized to obtain the composition compound library of Hedysari Radix.The three-dimensional structure of the inflammatory target TNFR1(PDB ID:1 TNR) was identified.After hydrotreating and anhydrating,the binding pocket residues were identified according to the literature.According to the defined target structure and binding pocket,the flexible molecular docking was conducted between the composition compound library and the target,and the score(Glide Score) was obtained.Based on the results of molecular docking,the first nine small molecular compounds of Glide Score were selected as candidate components.On this basis,the drug-likeness was analyzed,which involved small molecular compounds that meet the number of hydrogen-bonded receptors,the number of hydrogen-bonded donors,the formula weight,the number of rotatable key and the numerical range of lipo-hydro partition coefficient.Finally,the binding mode was analyzed according to pharmacokinetic parameters and complex structure of composition-target docking.Result:The residue set in the TNFR1 drug-binding pocket were identified as glutamic acid109(Glu109),lysine 35(Lys35),alanine62(Ala62),serine 74(Ser74),lysine75(Lys75),cysteine76(Cys76),argnine 77(Arg77),glutamine82(Gln82),threonine89(Thr89),asparticacid91(Asp91),argnine92(Arg92),aspartic acid93(Asp93),threonine 94(Thr94),valine95(Val95),cysteine 96(Cys96),argnine104(Arg104),tyrosine106(Tyr106),asparagine110(Asn110),leucine111(Leu111),phenylalanine112(Phe112),glutamic acid 131(Glu131)and lysine132(Lys132).Totally 43 small molecular compounds of Hedysari Radix were obtained.Five small molecular compounds,namely hedysari radix,quercetin,isoliquiritin,naringenin,calycosin and liquiritigenin,were screened by comprehensive factors,like docking scoring.Conclusion:Quercetin,isoliquiritin,naringenin,calycosin and liquiritigenin are the effective anti-inflammatory substances of Hedysari Radix,with a great possibility of becoming TNFR1 antagonists.
Objective:To study the effect of small molecule compounds of Hedysari Radix in ntagonizing tumor necrosis factor receptor type 1(TNFR1) based on molecular docking.Method:The structure of small molecular compound of Hedysari Radix was downloaded from the chemical composition compound library of traditional Chinese medicine,and then optimized to obtain the composition compound library of Hedysari Radix.The three-dimensional structure of the inflammatory target TNFR1(PDB ID:1 TNR) was identified.After hydrotreating and anhydrating,the binding pocket residues were identified according to the literature.According to the defined target structure and binding pocket,the flexible molecular docking was conducted between the composition compound library and the target,and the score(Glide Score) was obtained.Based on the results of molecular docking,the first nine small molecular compounds of Glide Score were selected as candidate components.On this basis,the drug-likeness was analyzed,which involved small molecular compounds that meet the number of hydrogen-bonded receptors,the number of hydrogen-bonded donors,the formula weight,the number of rotatable key and the numerical range of lipo-hydro partition coefficient.Finally,the binding mode was analyzed according to pharmacokinetic parameters and complex structure of composition-target docking.Result:The residue set in the TNFR1 drug-binding pocket were identified as glutamic acid109(Glu109),lysine 35(Lys35),alanine62(Ala62),serine 74(Ser74),lysine75(Lys75),cysteine76(Cys76),argnine 77(Arg77),glutamine82(Gln82),threonine89(Thr89),asparticacid91(Asp91),argnine92(Arg92),aspartic acid93(Asp93),threonine 94(Thr94),valine95(Val95),cysteine 96(Cys96),argnine104(Arg104),tyrosine106(Tyr106),asparagine110(Asn110),leucine111(Leu111),phenylalanine112(Phe112),glutamic acid 131(Glu131)and lysine132(Lys132).Totally 43 small molecular compounds of Hedysari Radix were obtained.Five small molecular compounds,namely hedysari radix,quercetin,isoliquiritin,naringenin,calycosin and liquiritigenin,were screened by comprehensive factors,like docking scoring.Conclusion:Quercetin,isoliquiritin,naringenin,calycosin and liquiritigenin are the effective anti-inflammatory substances of Hedysari Radix,with a great possibility of becoming TNFR1 antagonists.
引文
[1]Zaka M,Abbasi B H,Durdagi S.Proposing novel TNF-αdirect inhibitor Scaffolds using fragment-docking based e-pharmacophore modeling and binary QSAR-based virtual screening protocols pipeline[J].J Mol Graph Model,2018,85:111-121.
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[28]Khajevand-Khazaei M R,Ziaee P,Motevalizadeh S A,et al.Naringenin ameliorates learning and memory impairment following systemic lipopolysaccharide challenge in the rat[J].Eur J Pharmacol,2018,826:114-122.
[29]XU Y,FENG L,WANG S,et al.Calycosin protects HUVECs from advanced glycation end products-induced macrophage infiltration[J].J Ethnopharmacol,2011,137(1):359-370.
[30]GAO J,LIU Z J,CHEN T,et al.Pharmaceutical properties of calycosin,the major bioactive isoflavonoid in the dry root extract of Radix astragali[J].Pharm Biol,2014,52(9):1217-1222.
[31]YIN L,GUAN E,ZHANG Y,et al.Chemical profile and anti-inflammatory activity of total flavonoids from Glycyrrhiza uralensis Fisch[J].Iran J Pharm Res,2018,17(2):726-734
[32]YANG M,JIN Y,YANG L P.A systematic summary of natural compounds in Radix Glycyrrhizae[J].Tradit Med Res,2018,3(2):82-94.
[33]ZHU X,SHI J,LI H.Liquiritigenin attenuates high glucose-induced mesangial matrix accumulation,oxidative stress,and inflammation by suppression of the NF-κB and NLRP3 inflammasome pathways[J].Biomed Pharmacother,2018,106:976-982.
[34]GAO Y,GAO L,TIAN J S,et al.A network pharmacology approach to decipher the mechanisms of anti-depression of Xiaoyaosan formula[J].Chin JPharmacol Toxicol,2017,31(5):477.
[35]刘楠,姜云耀,黄婷婷,等.基于网络药理学方法研究补阳还五汤治疗脑梗死的作用机制[J].中国中药杂志,2018,43(11):2190-2198.
[36]GAO Y,GAO L,TIAN J S,et al.A network pharmacology approach to decipher the mechanisms of anti-depression of Xiaoyaosan formula[J].World J Trad Chin Med,2018,4(4):147.
[37]Zaka M,Abbasi B H,Durdagi S.Proposing novel TNF-αdirect inhibitor Scaffolds using fragment-docking based e-pharmacophore modeling and binary QSAR-based virtual screening protocols pipeline[J].J Mol Graph Model,2018,85:111-121.
[38]Comalada M,Camuesco D,Sierra S,et al.In vivo quercitrin anti-inflammatory effect involves release of quercetin,which inhibits inflammation through downregulation of the NF-kappaB pathway[J].Eur JImmunol,2010,35(2):584-592.
[39]Garcíamediavilla V,Crespo I,Collado P S,et al.The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase,cyclooxygenase-2 and reactive C-protein,and downregulation of the nuclear factor kappa B pathway in Chang Liver cells[J].Eur J Pharmacol,2007,557(2):221-229.
[40]Oliveira M R D,Fürstenau C R.Naringenin exerts antiinflammatory effects in paraquat-treated SH-SY5Y cells through a mechanism associated with the Nrf2/HO-1Axis[J].Neurochem Res,2018,43(4):894-903.
[41]Ko Y H,Kwon S H,Hwang J Y,et al.The memoryenhancing effects of liquiritigenin by activation of NMDAreceptors and the CREB signaling pathway in mice[J].Biomol Ther(Seoul),2018,26(2):109-114.
[42]Hsu Y L,KUO P L,LIN L T,et al.Isoliquiritigenin inhibits cell proliferation and induces apoptosis in human hepatoma cells[J].Planta Med,2005,71(2):130-134.
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[46]Crespo I,Garcíamediavilla M V,Gutiérrez B,et al.Acomparison of the effects of kaempferol and quercetin on cytokine-induced pro-inflammatory status of cultured human endothelial cells[J].Br J Nutr,2008,100(5):968-976.
[2]Uysal H,Chavez-Galan L,Vesin D,et al.Transmembrane TNF and partially TNFR1 regulate TNFR2 expression and control inflammation in mycobacterial-induced pleurisy[J].Int J Mol Sci,2018,19(7):1959.
[3]朱伟,姚丽梅.肿瘤坏死因子-α中药小分子抑制剂的计算机虚拟筛选[J].中国实验方剂学杂志,2010,16(13):199-202.
[4]万生芳,张凌伟,王晓丽,等.当归红芪超滤膜提取物对糖尿病肾病大鼠肾组织中NF-κB,TNF-α表达的影响[J].时珍国医国药,2018,29(1):27-30.
[5]李纬,程卫东,张文君,等.含红芪、黄芪的益气养血汤对SAMP8小鼠免疫衰老及p38 MAPK表达的影响[J].中国实验方剂学杂志,2016,22(24):105-110.
[6]孙美花,程卫东,张文君,等.含红芪与含黄芪的玉屏风散对SAMP8小鼠脾T细胞及PI3K表达的影响[J].中华中医药杂志,2017,32(3):1276-1280.
[7]杨欣,李亚辉,钱海兵,等.基于网络药理学及分子对接分析熊果酸抗类风湿性关节炎的分子机制[J].中国实验方剂学杂志,2018,24(18):207-214.
[8]Banner D W,D'Arcy A,Janes W,et al.Crystal structure of the soluble human 55 kd TNF receptor-human TNFbeta complex:implications for TNF receptor activation[J].Cell,1993,73(3):431-445.
[9]LI M,GONG H,ZHU H,et al.A novel small-molecule TNF-αinhibitor attenuates inflammation in a hepatitis mouse model[J].J Biol Chem,2014,289(18):12457-12466.
[10]Murali R,CHENG X,Berezov A,et al.Disabling TNFreceptor signaling by induced conformational perturbation of tryptophan-107[J].Proc Natl Acad Sci USA,2005,102(31):10970-10975.
[11]Mukai Y,Nakamura T,Yoshikawa M,et al.Solution of the structure of the TNF-TNFR2 complex[J].Sci Signal,2010,3(148):ra83.
[12]MA L,GONG H,ZHU H,et al.A novel smallmolecule tumor necrosis factorαinhibitor attenuates inflammation in a hepatitis mouse model[J].J Biol Chem,2014,289(18):12457-12466.
[13]Etemadi N,Holien J K,Chau D,et al.Lymphotoxinαinduces apoptosis,necroptosis and inflammatory signals with the same potency as tumour necrosis factor[J].FEBS J,2013,280(21):5283-5297.
[14]Christopher A L,Franco L,Beryl W D,et al.Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings[J].Adv Drug Deliv Rev,1997,23(1/3):3-26.
[15]Boesch-Saadatmandi C,Loboda A,Wagner A E,et al.Effect of quercetin and its metabolites isorhamnetin and quercetin-3-glucuronide on inflammatory gene expression:role of miR-155[J].J Nutr Biochem,2011,22(3):293-299.
[16]Kwon H M,Choi Y J,Choi J S,et al.Blockade of cytokine-induced endothelial cell adhesion molecule expression by licorice isoliquiritigenin through NF-kappa B signal disruption[J].Exp Biol Med(Maywood),2007,232(2):235-245.
[17]HAN N R,Moon P D,Ryu K J,et al.Inhibitory effect of naringenin via IL-13 level regulation on thymic stromal lymphopoietin-induced inflammatory reactions[J].Clin Exp Pharmacol Physiol,2017,45(4):362-369.
[18]Kim Y W,ZHAO R J,Park S J,et al.Anti-inflammatory effects of liquiritigenin as a consequence of the inhibition of NF-κB-dependent i NOS and proinflammatory cytokines production[J].Br J Pharmacol,2008,154(1):165-173.
[19]MA R,YUAN F,WANG S,et al.Calycosin alleviates cerulein-induced acute pancreatitis by inhibiting the inflammatory response and oxidative stress via the p38MAPK and NF-κB signal pathways in mice[J].Biomed Pharmacother,2018,105:599-605.
[20]Kumar K S,Sabu V,Sindhu G,et al.Isolation,identification and characterization of apigenin from Justicia gendarussa and its anti-inflammatory activity[J].Int Immunopharmacol,2018,59:157-167.
[21]ZOU H,ZHENG Y F,GE W,et al.Synergistic antitumour effects of quercetin and oncolytic adenovirus expressing TRAIL in human hepatocellular carcinoma[J].Sci Rep,2018,8(1):2182.
[22]刘艳飞.中药治疗代谢综合征的药物筛选及分子作用机制研究[D].北京:北京中医药大学,2018.
[23]ZHANG W,WANG G,ZHOU S.Protective effects of isoliquiritigenin on LPS-induced acute lung injury by activating PPAR-γ[J].Inflammation,2018,41(4):1290-1296.
[24]YU D,LIU X,ZHANG G,et al.Isoliquiritigenin inhibits cigarette smoke-induced COPD through attenuating inflammation and oxidative stress via regulating Nrf2 and NF-κB signaling pathways[J].Front Pharmacol,2018,doi:10.3389/fphar.2018.01001.
[25]Nakamura S,Watanabe T,Tanigawa T,et al.Isoliquiritigenin ameliorates indomethacin-induced small intestinal damage by inhibiting NOD-like receptor family,pyrin domain-containing 3 inflammasome activation[J].Pharmacology,2018,101(5/6):236-245.
[26]ZENG W,JIN L,ZHANG F,et al.Naringenin as a potential immunomodulator in therapeutics[J].Pharmacol Res,2018,135:122-126.
[27]Bansal Y,Singh R,Saroj P,et al.Naringenin protects against oxido-inflammatory aberrations and altered tryptophan metabolism in olfactory bulbectomized-mice model of depression[J].Toxicol Appl Pharmacol,2018,355:257-268.
[28]Khajevand-Khazaei M R,Ziaee P,Motevalizadeh S A,et al.Naringenin ameliorates learning and memory impairment following systemic lipopolysaccharide challenge in the rat[J].Eur J Pharmacol,2018,826:114-122.
[29]XU Y,FENG L,WANG S,et al.Calycosin protects HUVECs from advanced glycation end products-induced macrophage infiltration[J].J Ethnopharmacol,2011,137(1):359-370.
[30]GAO J,LIU Z J,CHEN T,et al.Pharmaceutical properties of calycosin,the major bioactive isoflavonoid in the dry root extract of Radix astragali[J].Pharm Biol,2014,52(9):1217-1222.
[31]YIN L,GUAN E,ZHANG Y,et al.Chemical profile and anti-inflammatory activity of total flavonoids from Glycyrrhiza uralensis Fisch[J].Iran J Pharm Res,2018,17(2):726-734
[32]YANG M,JIN Y,YANG L P.A systematic summary of natural compounds in Radix Glycyrrhizae[J].Tradit Med Res,2018,3(2):82-94.
[33]ZHU X,SHI J,LI H.Liquiritigenin attenuates high glucose-induced mesangial matrix accumulation,oxidative stress,and inflammation by suppression of the NF-κB and NLRP3 inflammasome pathways[J].Biomed Pharmacother,2018,106:976-982.
[34]GAO Y,GAO L,TIAN J S,et al.A network pharmacology approach to decipher the mechanisms of anti-depression of Xiaoyaosan formula[J].Chin JPharmacol Toxicol,2017,31(5):477.
[35]刘楠,姜云耀,黄婷婷,等.基于网络药理学方法研究补阳还五汤治疗脑梗死的作用机制[J].中国中药杂志,2018,43(11):2190-2198.
[36]GAO Y,GAO L,TIAN J S,et al.A network pharmacology approach to decipher the mechanisms of anti-depression of Xiaoyaosan formula[J].World J Trad Chin Med,2018,4(4):147.
[37]Zaka M,Abbasi B H,Durdagi S.Proposing novel TNF-αdirect inhibitor Scaffolds using fragment-docking based e-pharmacophore modeling and binary QSAR-based virtual screening protocols pipeline[J].J Mol Graph Model,2018,85:111-121.
[38]Comalada M,Camuesco D,Sierra S,et al.In vivo quercitrin anti-inflammatory effect involves release of quercetin,which inhibits inflammation through downregulation of the NF-kappaB pathway[J].Eur JImmunol,2010,35(2):584-592.
[39]Garcíamediavilla V,Crespo I,Collado P S,et al.The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase,cyclooxygenase-2 and reactive C-protein,and downregulation of the nuclear factor kappa B pathway in Chang Liver cells[J].Eur J Pharmacol,2007,557(2):221-229.
[40]Oliveira M R D,Fürstenau C R.Naringenin exerts antiinflammatory effects in paraquat-treated SH-SY5Y cells through a mechanism associated with the Nrf2/HO-1Axis[J].Neurochem Res,2018,43(4):894-903.
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