骨愈灵胶囊活性成分治疗骨质疏松的生物信息学分析

Exploring effective components of Guyuling capsule in the treatment of osteoporosis based on bioinformatics analysis

背景:临床研究表明骨愈灵胶囊对骨质疏松症治疗有效,但作用机制不明确。目的:文章旨在通过生物信息学中的分子对接技术筛选骨愈灵胶囊中作用于骨质疏松症相关靶蛋白的活性成分。方法:利用中药系统药理学数据库及分析平台(TCMSP)和中药综合数据库(TCMID)筛选骨愈灵胶囊中的化学成分,筛选条件为生物利用度≥20%,类药性值≥0.18。根据文献和数据库记载构建骨质疏松症相关靶蛋白库。通过Discovery Studio 2016(DS 2016)软件进行药物的吸收、分布、代谢、排泄和毒性(Absorption,Distribution,Metabolism,Excretion,Toxicity,ADMET)预测和分子对接。结果与结论:(1)在中药数据库中筛选并下载骨愈灵胶囊的生物利用度较好的潜在活性成分130个,通过Discovery Studio 2016软件的ADMET预测功能筛选得到63个吸收良好、低毒性的活性成分,如L-α-甘油棕榈酸酯、芝麻素等;(2)通过查阅文献和数据库,选取与骨质疏松有确切相关性的17个膜蛋白受体,如对细胞生长分化具有调节作用的细胞外信号调节激酶1/2(ERK1/2)、AKT、糖原合成酶激酶3β(GSK3β)等;主要与有丝分裂原激活的蛋白激酶信号通路、骨形态发生蛋白信号通路等通路有关,可能通过调节间充质干细胞的生长和分化,促进骨形成;(3)分子对接结果表明苏式-二羟基脱氢二松柏醇、(23E)-20,25-二羟基达玛-23-烯-3-酮、L-α-甘油棕榈酸酯、芝麻素、(24S)-20,24-环氧-25-羟基达玛树脂-3-酮与细胞外信号调节激酶1/2、蛋白激酶、糖原合成酶激酶3等膜蛋白具有较高对接得分,可能主要通过调节丝裂原活化蛋白激酶信号通路治疗骨质疏松;(4)上述结果证实,骨愈灵胶囊中的活性成分苏式-二羟基脱氢二松柏醇、(23E)-20,25-二羟基达玛-23-烯-3-酮、L-α-甘油棕榈酸酯、芝麻素、(24S)-20,24-环氧-25-羟基达玛树脂-3-酮可能通过与细胞外信号调节激酶1/2、蛋白激酶、糖原合成酶激酶3β等膜蛋白结合,调控丝裂原活化蛋白激酶、骨形态发生蛋白、Wnt、雌激素受体等信号通路,进而发挥治疗骨质疏松的疗效,为进一步展开相关实验研究提供大数据分析基础及思路。

BACKGROUND:Clinical studies have shown that Guyuling capsule is effective in the treatment of osteoporosis,but the mechanism is not clear.OBJECTIVE:To screen out the active components acting on osteoporosis-related target proteins in Guyuling capsule by molecular docking technique in bioinformatics.METHODS:The chemical components of Guyuling capsule were screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database(TCMSP)and traditional Chinese medicine comprehensive database(TCMID).The screening conditions were bioavailability≥20%and drug likeness≥0.18.The target protein library related to osteoporosis was constructed according to the literature and database.Drug absorption,distribution,metabolism,excretion and toxicity(ADMET)prediction and molecular docking were carried out by Discovery Studio 2016 software.RESULTS AND CONCLUSION:(1)In total 130 potential active components with good bioavailability of Guyuling capsule were screened and downloaded from traditional Chinese medicine database.Sixty-three active components with good absorption and low toxicity were screened by ADMET prediction function of Discovery Studio 2016,such as L-α-glycerol palmitate,sesamin and so on.(2)By consulting the literature and database,17 membrane protein receptors were selected,such as extracellular signal-regulated kinase 1/2,protein kinase,and glycogen synthase kinase-3,which are definitely related to osteoporosis.It is mainly related to mitogen-activated protein kinase signal pathway and bone morphogenetic protein signal pathway,which may promote bone formation by regulating the growth and differentiation of mesenchymal stem cells.(3)The results of molecular docking showed high docking scores between Sudihydrodehydropineol,(23 E)-20,25-dihydrodama-23-en-3-one,L-α-glycerol palmitate,sesamin,(24 S)-20,24-epoxy-25-hydroxydama resin-3-one and extracellular signal-regulated kinase 1/2,protein kinase,glycogen synthase kinase-3 and other membrane proteins.Osteoporosis may be treated by mainly regulating mitogen-activated protein kinase signaling pathway.(4)The above results confirm that the active components of Guyuling capsule,such as Su-typedihydrodehydropineol,(23 E)-20,25-dihydroxydama-23-en-3-one,L-α-glycerol palmitate,sesamin,(24 S)-20,24-epoxy-25-hydroxydama resin-3-one,may bind to membrane proteins such as extracellular signal-regulated kinase 1/2,protein kinase and glycogen synthase kinase-3 beta to regulate mitogen-activated protein kinase,bone morphogenetic protein,Wnt,estrogen receptor and other signal pathways,and then play the therapeutic efficacy on osteoporosis,thereby providing big data analysis basis and ideas for further experimental research.