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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:Primary hypertension is understood as a disease with diverse etiology, a complicated pathological mechanism, and progressive changes. Gedan Jiangya Decoction (GJD), with the patent publication number CN114246896A, was designed to treat primary hypertension. It contains six botanical drugs; however, the underlying mechanism is uncertain. We utilized network pharmacology to predict the active components, targets, and signaling pathways of GJD in the treatment of primary hypertension. We also investigated the potential molecular mechanism using molecular docking and animal experiments. The Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), the Protein Database (UniProt), and a literature review were used to identify the active components and related targets of GJD's pharmacological effects. The GeneCards, Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD), and DrugBank databases were utilized to identify hypertension-related targets. Based on a Venn diagram of designed intersection targets, 214 intersection targets were obtained and 35 key targets for the treatment of hypertension were determined using the STRING data platform and Cytoscape software. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of key targets revealed that the relevant molecular action pathways of GJD in the treatment of hypertension include the Toll-like receptor, MAPK, PI3K-Akt, and renin-angiotensin signaling pathways. A GJD active ingredient-key target-pathway connection diagram was created using Cytoscape software, and 11 essential active components were selected. Molecular docking was then used to verify the binding activity of key targets and key active ingredients in GJD to treat primary hypertension. The results of this study indicate that AGTR1, AKT1 with puerarin, EDNRA with tanshinone IIA, MAPK14 with daidzein, MAPK8 with ursolic acid, and CHRM2 with cryptotanshinone had high binding activity to the targets with active components, whereas AGTR1 was selected as target genes verified by our experiment. HPLC was utilized to identify the five active ingredients. Experiments in high-salt rats demonstrated that GJD might decrease the expression of AGTR1 in the kidney and thoracic aorta while increasing the expression of eNOS by preventing the activation of the renin-angiotensin pathway, thereby reducing lowering systolic and diastolic blood pressure.

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:In this study, network pharmacology and molecular docking technology were used to explore the molecular mechanisms of the Duhuo Jisheng decoction in the treatment of osteoarthritis (OA). The chemical composition of the prescriptions was obtained from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) database and the retrieved literature. Targets for the active ingredients were obtained using TCMSP and the Swiss Target Prediction Database. Disease targets were obtained from GeneCards and DisGeNET databases. The online tool, Venny, was used to obtain common targets for drugs and diseases. Protein-protein interactions (PPI) between common targets were analyzed using the search tool for the retrieval of interacting genes/proteins (STRING) database. Common targets were analyzed for gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment using the database for annotation, visualization and integrated discovery (DAVID) database. Molecular docking of the first 10 targets and first 10 components was verified using AutoDock Tools software, and the docking diagram was visualized using PyMOL software. After screening, 210 chemical components of the Duhuo Jisheng decoction (DHJSD) were identified. The 253 common targets of drugs and diseases were combined by eliminating repeat values. Based on PPI network analysis, the top ten targets were SRC, STAT3, MAPK3, MAPK1, RELA, PIK3R1, HSP90AA1, TP53, EP300, and AKT1. KEGG analysis showed that DHJSD could regulate the HIF-1, PI3K-Akt, and JAK-STAT signaling pathways. The biological processes involved include inflammatory reactions, the negative regulation of apoptosis, and the positive regulation of cell proliferation. Molecular docking results showed that all targets, except the RELA protein, showed good binding to the compounds, indicating that the 10 components might exert therapeutic effects by binding to the above targets. DHJSD can treat OA by regulating the HIF-1, PI3K-Akt, and JAK-STAT signaling pathways. The proteins involved were SRC, STAT3, MAPK3, MAPK1, and PIK3R1. In this study, network pharmacology was used to predict the mechanism of DHJSD in OA treatment, which was verified by molecular docking to provide experimental research ideas and scientific basis for OA treatment.

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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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