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Chemical composition and therapeutic mechanism of Xuanbai Chengqi Decoction in the treatment of COVID-19 by network pharmacology, molecular docking and molecular dynamic analysis.

ABSTRACT: Xuanbai Chengqi Decoction (XBCQD), a classic traditional Chinese medicine, has been widely used to treat COVID-19 in China with remarkable curative effect. However, the chemical composition and potential therapeutic mechanism is still unknown. Here, we used multiple open-source databases and literature mining to select compounds and potential targets for XBCQD. The COVID-19 related targets were collected from GeneCards and NCBI gene databases. After identifying putative targets of XBCQD for the treatment of COVID-19, PPI network was constructed by STRING database. The hub targets were extracted by Cytoscape 3.7.2 and MCODE analysis was carried out to extract modules in the PPI network. R 3.6.3 was used for GO enrichment and KEGG pathway analysis. The effective compounds were obtained via network pharmacology and bioinformatics analysis. Drug-likeness analysis and ADMET assessments were performed to select core compounds. Moreover, interactions between core compounds and hub targets were investigated through molecular docking, molecular dynamic (MD) simulations and MM-PBSA calculations. As a result, we collected 638 targets from 61 compounds of XBCQD and 845 COVID-19 related targets, of which 79 were putative targets. Based on the bioinformatics analysis, 10 core compounds and 34 hub targets of XBCQD for the treatment of COVID-19 were successfully screened. The enrichment analysis of GO and KEGG indicated that XBCQD mainly exerted therapeutic effects on COVID-19 by regulating signal pathways related to viral infection and inflammatory response. Meanwhile, the results of molecular docking showed that there was a stable binding between the core compounds and hub targets. Moreover, MD simulations and MM-PBSA analyses revealed that these compounds exhibited stable conformations and interacted well with hub targets during the simulations. In conclusion, our research comprehensively explained the multi-component, multi-target, and multi-pathway intervention mechanism of XBCQD in the treatment of COVID-19, which provided evidence and new insights for further research.

SUBMITTER: Fan L

PROVIDER: S-EPMC8902854 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveThis study aimed to explore the mechanism of Modified Danggui Sini Decoction in the treatment of knee osteoarthritis via a combination of network pharmacology and molecular docking.MethodsThe main chemical components and corresponding targets of Modified Danggui Sini Decoction were searched and screened in TCMSP database. The disease targets of knee osteoarthritis were summarized in GeneCards, OMIM, PharmGkb, TTD, and DrugBank databases. The visual interactive network of "drugs-active components-disease targets" was drawn by Cytoscape 3.8.1 software. The protein-protein interaction network was constructed by STRING database. Then, GO function and KEGG pathway enrichment were analyzed by Bioconductor/R, and the pathway of the highest degree of correlation with knee osteoarthritis was selected for specific analysis. Finally, molecular docking was used to screen and verify core genes by AutoDockTools software.ResultsSeventy-one main components of Modified Danggui Sini Decoction and 116 potential therapeutic targets of knee osteoarthritis were selected. The KEGG pathway and the GO function enrichment analysis showed that the targets of Modified Danggui Sini Decoction in the treatment of knee osteoarthritis were mainly concentrated on PI3K-Akt signaling pathway, TNF signaling pathway, IL-17 signaling pathway, apoptosis signaling pathway, Toll-like receptor signaling pathway, Th17 cell differentiation signaling pathway, HIF-1 signaling pathway, and NF-κB signaling pathway. It mainly involved inflammatory reaction, regulation of apoptotic signaling pathway, cellular response to regulation of inflammatory response, cellular response to oxidative stress, and other biological processes. The molecular docking results showed that ESR1-wogonin, MAPK1-quercetin, RELA-wogonin, RELA-baicalein, TP53-baicalein, TP53-quercetin, and RELA-quercetin have strong docking activities.ConclusionModified Danggui Sini Decoction has the hierarchical network characteristics of "multicomponent, multitarget, multifunction, and multipathway" in the treatment of knee osteoarthritis. It mainly regulates the proliferation and apoptosis of chondrocytes by regulating the PI3K-Akt signaling pathway and establishes cross-talk with many downstream inflammatory-related pathways to reduce the overall inflammatory response. Meanwhile, HIF-1 expression was used to ensure the normal function and metabolism of knee joint under hypoxia condition, and the above processes play a key role in the treatment of knee osteoarthritis.

Project description:BackgroundDue to unhealthy diet and living habits, the incidence of gout is on the rise and has become a common disease with a high incidence. Danggui Niantong decoction (DGNTD), as a classic formula composed of 15 common herbs, has been widely used in clinical practice since ancient times to prevent and treat gout. However, the pharmacological mechanism and target of DGNTD are not clear.MethodsThe potential active compounds and targets of DGNTD were obtained by traditional Chinese medicine systems pharmacology (TCMSP) database, and the differential genes of gout patients and controls were analyzed in gene expression omnibus (GEO) database. GSEA analysis of differential genes with GSEA 4.1.0 software and then the differential genes were intersected with the gout-related disease targets searched by GeneCard, CTD and OMIM disease database to obtain the final disease target. The "Traditional Chinese medicine-Active compounds-Targets" network was constructed by Cytoscape3.7.2 software. The R packet is used for enrichment analysis. The molecular docking between the active compound of DGNTD and the core target was verified by AutoDockTools software.ResultsTwo hundred eighty six and 244 targets of DGNTD-related active components and 652 targets of gout were obtained, of which 13 targets were potential targets of DGNTD in the treatment of gout. GSEA analysis showed that the differential genes were mainly involved in apoptosis, inflammatory reaction, and receptor metabolism and so on. Gene ontology (GO) functional enrichment analysis shows that DGNTD regulates many biological processes, such as the response to purine-containing compound and response to lipopolysaccharide, positive regulation of acute inflammatory response and other cellular components. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis shows that DGNTD treatment of gout is mainly related to interleukin-17 (IL-17), Toll-like receptor, rheumatoid arthritis, tumor necrosis factor (TNF) and so on. The results of molecular docking showed that the five active compounds in DGNTD had strong binding activity to core protein receptors.ConclusionsThe active compounds of DGNTD may achieve the purpose of treating gout by acting on the core target (CASP8, CXCL8, FOS, IL1B, IL6, JUN, PTGS2, STAT1, MMP1, TNF) to regulate cell metabolism, proliferation and apoptosis, and improve inflammatory response, which is the result of multi-component, multi-target and multi-pathway interaction. It provides an idea for the development of new combined drugs for gout.

Project description:Ulcerative colitis (UC) is a disease with complex pathological mechanisms. We explored the potential molecular mechanisms behind the therapeutic functions of Qingzi Zhitong decoction (QZZTD) in the treatment of UC by network pharmacology and molecular docking. QZZTD is a formula of Chinese traditional medicine consisting of 10 herbs. The potential active ingredients of QZZTD and their target genes were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database, and UC-related target genes were obtained from GeneCards and OMIM databases. A total of 138 co-identified target genes were obtained by plotting the intersection target Venn diagram, and then the STRING database and Cytoscape software were used to establish protein-protein interaction networks and herb-ingredient-target networks. Four key active compounds and nine key proteins were identified. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that the biological functions of potential target genes were associated with DNA transcription, signaling receptor and ligand activity, cytokine activity, cellular autophagy, and antioxidant pathways, with related pathways involving the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway, advanced glycosylation end product (AGE)-RAGE signaling pathway, tumor necrosis factor (TNF) signaling pathway, and IL-17 signaling pathway. Moreover, the binding activities of key target genes and essential active compounds of Chinese herbal medicines in QZZTD were further validated by molecular docking. This demonstrated that quercetin, luteolin, hyndarin, and beta-sitosterol had good binding to eight key proteins, and Akt1 was the target protein with the best binding activity, suggesting that Akt1 could be the essential mediator responsible for signaling transduction after QZZTD administration. The rat experiment verified that QZZTD inhibited PI3K-Akt pathway activation and reduced inflammation in UC. In conclusion, our study suggested four potential key active components, including quercetin, were identified in QZZTD, which could interact with Akt1 and modulate the activation of the PI3K-Akt pathway. The other three pathways may also be involved in the signaling transduction induced by QZZTD in the treatment of UC.

Project description:Objective: Colon cancer is a malignant neoplastic disease that seriously endangers the health of patients. Pulsatilla decoction (PD) has some therapeutic effects on colon cancer. This study is based on the analytical methods of network pharmacology and molecular docking to study the mechanism of PD in the treatment of colon cancer. Methods: Based on the Traditional Chinese Medicine Systems Pharmacology Database, the main targets and active ingredients in PD were filtered, and then, the colon cancer-related targets were screened using Genecards, OMIM, PharmGKB, and Drugbank databases. Then, the screened drug and disease targets were Venn analyzed to obtain the intersection targets. Cytoscape software was used to construct the "Components-Targets-Pathway" map, and the String database was used to analyze the protein interaction network of the intersecting targets and screen the core targets, and then, the core targets were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Molecular docking was implemented using AutoDockTools to predict the binding capacity for the core targets and the active components in PD. Results: Sixty-five ingredients containing 188 nonrepetitive targets were screened and 180 potential targets of PD anticolon cancer were identified, including 10 core targets, namely, MAPK1, JUN, AKT1, TP53, TNF, RELA, MAPK14, CXCL8, ESR1, and FOS. The results of GO analysis showed that PD anticolon cancer may be related to cell proliferation, apoptosis, energy metabolism, immune regulation, signal transduction, and other biological processes. The results of KEGG analysis indicated that the PI3K-Akt signaling pathway, MAPK signaling pathway, proteoglycans in cancer, IL-17 signaling pathway, cellular senescence, and TNF signaling pathway were mainly involved in the regulation of tumor cells. We further selected core targets with high degree values as receptor proteins for molecular docking with the main active ingredients of the drug, including MAPK1, JUN, and AKT1. The docking results showed good affinity, especially quercetin. Conclusion: This study preliminarily verified that PD may exert its effect on the treatment of colon cancer through multi-ingredients, multitargets, and multipathways. This will deepen our understanding of the potential mechanisms of PD anticolon cancer and establish a foundation for further basic experimental research.

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Chemical composition and therapeutic mechanism of Xuanbai Chengqi Decoction in the treatment of COVID-19 by network pharmacology, molecular docking and molecular dynamic analysis.

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