目的 基于網(wǎng)絡(luò)藥理學和分子對接技術(shù)探討護骨膠囊治療骨質(zhì)疏松癥潛在的活性成分和作用機制。方法 利用TCMSP數(shù)據(jù)庫結(jié)合《中國藥典》2020版篩選候選活性成分，并通過文獻檢索進行補充和刪減得到最終成分，并通過Swiss Target Prediction數(shù)據(jù)庫預(yù)測和篩選出活性成分的潛在的作用靶點。通過權(quán)威數(shù)據(jù)庫（Genecard、Drugbank、TTD）檢索骨質(zhì)疏松癥相關(guān)靶點，通過Cytoscape 3.9.0軟件建立中藥–成分–靶點網(wǎng)絡(luò)模型進行網(wǎng)絡(luò)分析，并將交集靶點導入至String在線數(shù)據(jù)庫進行蛋白相互作用（PPI）網(wǎng)絡(luò)構(gòu)建并進行分析。利用David數(shù)據(jù)庫進行基因本體論（GO）和京都基因與基因組百科全書（KEGG）通路富集分析。利用AutoDockTools 1.5.6軟件進行分子對接。結(jié)果 共篩選出護骨膠囊59個活性成分、78個交集靶點。PPI網(wǎng)絡(luò)分析表明，腫瘤壞死因子（TNF）、血管內(nèi)皮生長因子A（VEGFA）、非受體酪氨酸激酶（SRC）、酪氨酸蛋白激酶3（MAPK3）、雌激素受體α（ESR1）等可能是護骨膠囊治療骨質(zhì)疏松癥的關(guān)鍵靶點。GO和KEGG富集分析表明護骨膠囊主要通過細胞外空間、質(zhì)膜、宿主細胞核等細胞組分參與細胞生存、生長、分裂等眾多生物學過程，繼而與蛋白質(zhì)特異性結(jié)合，發(fā)揮調(diào)節(jié)核受體活性、過渡金屬離子結(jié)合、類固醇結(jié)合等分子功能，涉及糖尿病并發(fā)癥中的晚期糖基化終末化產(chǎn)物（AGE）-晚期糖基化終末產(chǎn)物受體（RAGE）信號通路、松弛素信號通路、雌激素信號通路等。分子對接結(jié)果表明，地黃苦苷元、大黃素甲醚、甲基異茜草素、阿魏酸和大豆苷元核心成分與TNF、VEGFA、SRC、MAPK3、ESR1核心靶點均具有良好的結(jié)合能力。結(jié)論 護骨膠囊中的地黃苦苷元、大黃素甲醚、甲基異茜草素、阿魏酸和大豆苷元等可能是治療骨質(zhì)疏松癥的物質(zhì)基礎(chǔ)，能夠作用于TNF、VEGFA、SRC、MAPK3、ESR1等多個靶點，通過調(diào)節(jié)糖尿病并發(fā)癥中的AGE-RAGE信號通路、松弛素信號通路、雌激素信號通路等參與骨骼重塑、抑制破骨細胞的形成與分化、促進骨形成和抗炎作用，進而發(fā)揮治療骨質(zhì)疏松癥的作用。

Objective To explore the potential active ingredients and mechanism of Hugu Capsules in treating osteoporosis based on network pharmacology and molecular docking technology. Methods The candidate active ingredients were screened using TCMSP database in combination with the 2020 edition of Chinese Pharmacopoeia, and the final ingredients were obtained through supplement and deletion through literature search, and the potential targets of active ingredients were predicted and screened through the Swiss Target Prediction database. The targets related to osteoporosis were searched through authoritative databases (Genecard, Drugbank, TTD), and the TCM - component - target network model was established by Cytoscape 3.9.0 software for network analysis. The intersection targets were imported into the String online database for protein interaction (PPI) network construction and analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using the David database. Molecular docking was performed using AutoDockTools 1.5.6 software. Results A total of 59 active components and 78 intersection targets of Hugu Capsules were screened out. PPI network analysis showed that TNF, VEGFA, SRC, MAPK3, and ESR1 may be the key targets of Hugu Capsules in treatment of osteoporosis. GO and KEGG enrichment analysis showed that Hugu Capsules mainly participated in many biological processes such as cell survival, growth and division through extracellular space, plasma membrane, host nucleus and other cell components, and then specifically bound to proteins to regulate nuclear receptor activity, transition metal ion binding, steroid binding and other molecular functions, involving AGE-RAGE signaling pathway, relaxin signaling pathway and estrogen signaling pathway in diabetic complications. The results of molecular docking showed that the core components such as rehmannia aglycone, physcion, methyl isoalizarin, ferulic acid, and daidzein had good binding ability to core targets such as TNF, VEGFA, SRC, MAPK3, and ESR1. Conclusion Rehmanniogenin, physcion, methylisoalizarin, ferulic acid, and daidzein in Hugu Capsules may be the material basis for the treatment of osteoporosis, which can act on multiple targets such as TNF, VEGFA, SRC, MAPK3, and ESR1, and participate in bone remodeling, inhibit the formation and differentiation of osteoclasts, promote bone formation and anti-inflammatory effects by regulating AGE-RAGE signaling pathway, relaxin signaling pathway and estrogen signaling pathway in diabetic complications, and then play a role in treatment of osteoporosis.

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國家自然科學基金資助項目(82174147);廣東省基礎(chǔ)與應(yīng)用基礎(chǔ)研究基金項目(2021A1515011271,2023A515011686);廣東省中醫(yī)藥局科研項目(20213019);第七批全國名老中醫(yī)藥專家學術(shù)經(jīng)驗繼承項目[國中醫(yī)藥人教函(2022)76號]