白术中白术内酯Ⅰ、Ⅱ、Ⅲ的靶标预测及蛋白互作网络研究
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摘要
目的:探究白术中白术内酯Ⅰ、Ⅱ、Ⅲ的潜在靶标及药理机制,为白术内酯类药物的研究开发提供网络药理学理论线索。方法:利用药效团匹配靶标服务器PharmMapper虚拟筛选白术内酯Ⅰ、Ⅱ、Ⅲ的潜在靶标,借助STRING平台构建靶蛋白互作网络并筛选关键靶标,利用治疗靶标数据库探究靶标的功能以及与通路、疾病的关系,采用系统分子对接服务器SystemsDock将白术内酯Ⅰ、Ⅱ、Ⅲ与关键靶标进行分子对接,验证白术内酯Ⅰ、Ⅱ、Ⅲ与关键靶标的亲和活性。结果:白术内酯Ⅰ、Ⅱ、Ⅲ主要作用于丝裂原激活蛋白激酶(MAPK)8、半胱氨酸蛋白酶(CASP)3、过氧化物酶体增殖物激活受体(PPARG)、一氧化氮合酶(NOS)3、热休克蛋白(HSP)90AA1、雌激素受体(ESR)1、雄激素受体(AR)、糖原合成酶激酶(GSK)3B、骨形态发生蛋白(BMP)2、凝血酶原前体片段F2等10个关键靶标,具有治疗肿瘤、心血管疾病、中枢神经系统疾病的潜在药理活性;除白术内酯Ⅰ与MAPK8的亲和力小于4.25外,白术内酯Ⅰ、Ⅱ、Ⅲ与对应靶标对接分数基本都在4.25以上,均属于有效结合。结论:白术内酯Ⅰ、Ⅱ、Ⅲ具有"多靶点、多通路、多疾病"的药理作用机制。
OBJECTIVE:To explore the potential target and pharmacological mechanism of atractylenolide Ⅰ,Ⅱ and Ⅲ in Atractylodes macrocephala, and to provide network pharmacology theoretical clues for further research and development of alicolactone. METHODS:The potential target of atractylenolide Ⅰ,Ⅱ and Ⅲ were screened by pharmacophore matching target server PharmMapper,and STRING platform was adopted to establish protein mutual network and screen key target. Therapeutic targets database was used to explore the function of the target and its relationship with pathways and diseases. Molecular docking server SystemsDock was used to dock the atractylenolide Ⅰ,Ⅱ,and Ⅲ with key targets to verify the affinity of atractylenolide Ⅰ,Ⅱ,and Ⅲ with key targets. RESULTS:Atractylenolide Ⅰ,Ⅱ,and Ⅲ mainly acted on 10 key targets such as MAPK8,CASP3,PPARG, NOS3, HSP90 AA1, ESR1, AR, GSK3 B, BMP2, prothrombin precursor fragment F2, showing potential pharmacological activity in the treatment of tumor,cardiovascular disease and central nervous system disease. Except that the affinity between atractylenolide Ⅰ and MAPK8 was less than 4.25,the docking scores of atractylenolide Ⅰ,Ⅱ,and Ⅲ with the corresponding target were basically above 4.25,and were valid. CONCLUSIONS:Atractylenolide Ⅰ,Ⅱ,and Ⅲ have the pharmacological mechanism of"multiple targets,multiple pathways,and multiple diseases".
OBJECTIVE:To explore the potential target and pharmacological mechanism of atractylenolide Ⅰ,Ⅱ and Ⅲ in Atractylodes macrocephala, and to provide network pharmacology theoretical clues for further research and development of alicolactone. METHODS:The potential target of atractylenolide Ⅰ,Ⅱ and Ⅲ were screened by pharmacophore matching target server PharmMapper,and STRING platform was adopted to establish protein mutual network and screen key target. Therapeutic targets database was used to explore the function of the target and its relationship with pathways and diseases. Molecular docking server SystemsDock was used to dock the atractylenolide Ⅰ,Ⅱ,and Ⅲ with key targets to verify the affinity of atractylenolide Ⅰ,Ⅱ,and Ⅲ with key targets. RESULTS:Atractylenolide Ⅰ,Ⅱ,and Ⅲ mainly acted on 10 key targets such as MAPK8,CASP3,PPARG, NOS3, HSP90 AA1, ESR1, AR, GSK3 B, BMP2, prothrombin precursor fragment F2, showing potential pharmacological activity in the treatment of tumor,cardiovascular disease and central nervous system disease. Except that the affinity between atractylenolide Ⅰ and MAPK8 was less than 4.25,the docking scores of atractylenolide Ⅰ,Ⅱ,and Ⅲ with the corresponding target were basically above 4.25,and were valid. CONCLUSIONS:Atractylenolide Ⅰ,Ⅱ,and Ⅲ have the pharmacological mechanism of"multiple targets,multiple pathways,and multiple diseases".
引文
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[2]国家药典委员会.中华人民共和国药典:一部[S].2015年版.北京:中国医药科技出版社,2015:103.
[3]HPLC-DAD波长切换法同时测定白术中白术内酯Ⅰ、Ⅱ、Ⅲ和苍术酮的含量[J].中华中医药杂志,2013,28(1):233-236.
[4]张金莲,谢日健,刘明贵,等.不同炮制方法对白术中白术内酯Ⅰ、Ⅱ、Ⅲ含量的影响[J].中国实验方剂学杂志,2016,22(21):15-18.
[5]吴慧,赵文龙,单国顺,等.HPLC波长切换法同时测定白术及其不同麸制品中白术内酯Ⅰ、Ⅱ、Ⅲ[J].中成药,2013,35(11):2484-2487.
[6]彭腾,李鸿翔,邓赟,等.白术内酯类成分及其药理作用研究进展[J].中国药房,2012,23(39):3732-3734.
[7]沈国庆,何法霖,李凤新,等.白术挥发油化学成分及抗肿瘤实验研究[J].北京中医药大学学报,2009,32(6):413-415.
[8]潘利文,宋捷.白术内酯Ⅰ体内外的抗黑色素瘤研究[J].中国医院药学杂志,2015,35(8):682-685.
[9]罗兰,孙悦.白术内酯Ⅲ对神经细胞损伤的影响[J].时珍国医国药,2012,23(3):560-562.
[10]李梢.网络靶标:中药方剂网络药理学研究的一个切入点[J].中国中药杂志,2011,36(15):2017-2020.
[11]HOPKINS AL.Network pharmacology[J].Nat Biotechnol,2007,25(10):1110-1111.
[12]韩春艳,李燕,刘刚,等.类药性:预测与实践[J].化学进展,2008,20(9):1135-1344.
[13]LIPINSKI CA,LOMBARDO F,DOMINY BW,et al.Experimental and computational approaches to estimate solubility and permeability in drug discovery[J].Adv Drug Delivery Rev,1997,46(1):3-26.
[14]LIU X,OUYANG S,YU B,et al.PharmMapper server:a web server for potential drug target identification using pharmacophore mapping approach[J].Nucleic Acids Res,Δ2010,38(Web Server issue):W609-W614.
[15]VON MERING C,JENSEN LJ,SNEL B,et al.STRING:known and predicted-protein protein associations,integrated and transferred across organisms[J].Nucleic Acids Res,2005,33(Database issue):D433-D437.
[16]薛潇春,胡晋红.网络药理学的研究方法与应用进展[J].药学实践杂志,2015,33(5):401-405.
[17]LI YH,YU CY,LI XX,et al.Therapeutic target database update 2018:enriched resource for facilitating bench-toclinic research of targeted therapeutics[J].Nucleic Acids Res,2018,46(D1):D1121-D1127.
[18]HSIN KY,MATSUOKA Y,ASAI Y,et al.SystemsDock:a web server for network pharmacology-based prediction and analysis[J].Nucleic Acids Res,2016,44(W1):W507-W513.
[19]陈一竹,杨文龙,郭玲玉,等.白术内酯3抗血小板作用及其机制[J].国际药学研究杂志,2016,43(3):514-517.
[20]张彩霞,张亚杰,江滨,等.白术内酯Ⅱ促进大肠癌Lovo细胞凋亡及对PARP1和Caspase-3表达的影响[J].中国实验方剂学杂志,2017,23(5):157-161.
[21]郭晴晴,李立,何小鹃,等.白术黄芪汤分子网络及细胞免疫作用的生物信息学分析[J].中国实验方剂学杂志,2016,22(14):206-210.
[22]赵刚,姜亚欣,迟玉花.白术治疗慢传输型便秘的研究进展[J].青岛大学医学院学报,2017,53(1):124-126.
[23]李多,于永强,高会斌,等.白术内酯Ⅰ对慢性萎缩性胃炎大鼠胃黏膜保护作用[J].河北中医药学报,2016,31(3):5-8.
[24]王嫦鹤,耿庆光,王雨轩.白术内酯Ⅰ对免疫性肝损伤的保护作用[J].中国中药杂志,2012,37(12):1809-1813.
[25]赵玉娇,高耀,周玉枝,等.白术在神经精神系统疾病中的药理作用及机制研究进展[J].中草药,2017,48(21):4546-4551.