Therapeutic Target Database Research Articles

Molecular docking, network pharmacology and experimental verification to explore the mechanism of Wulongzhiyangwan in the treatment of pruritus

Wulongzhiyangwan (WLZYW) is a Chinese prescription medicine for the treatment of pruritus, but its mechanism has not been clarified. The purpose of this study was to explore the mechanism of WLZYW in pruritus through network pharmacology analysis and experimental validation. The active components and corresponding targets of WLZYW were obtained from the Traditional Chinese Medicine Systematic Pharmacology (TCMSP) database. Pruritus-related targets were obtained from the GeneCards, TTD (Therapeutic Target Database), and DrugBank databases. The key compounds, core targets, main biological processes and signaling pathways related to WLZYW were identified by constructing and analyzing related networks. The binding affinity between WLZYW components and core targets was validated by AutoDock Vina software. In this study, RBL-2H3 cells were used to construct a degranulation model to simulate histamine-dependent pruritus. 10 chemical constituents, 235 targets and 3606 pruritus-related targets of WLZYW were obtained. Subsequently, 26 core targets were identified through analysis, VEGFA and AKT1 were the main candidates. A pathway enrichment analysis showed that overlapping targets were significantly enriched in the PI3K/AKT signaling pathway. A molecular docking analysis revealed tight binding of VEGF to three core compounds, kaempferol, luteolin and quercetin. Experiments showed that WZLYW inhibited mast cell degranulation, regulated VEGFa mRNA and protein expression levels by inhibiting PI3K/AKT and ERK1/2 signaling pathway activation. The mechanism of WZLYW in pruritus may be regulating VEGFa expression. Network pharmacology assays suggested that WLZYW downregulates VEGFa expression by regulating the PI3K/AKT and ERK1/2 signaling pathways in pruritis treatment.

Network Pharmacology and Molecular Docking Explore the Mechanism of Mubiezi-Yinyanghuo Herb Pair in the Treatment of Rheumatoid Arthritis.

Our previous studies have shown that the Mubiezi-Yinyanghuo (MBZ-YYH) herb pair inhibits rheumatoid arthritis (RA) cell proliferation and glycolysis, promising results with an obscure mechanism of action. Therefore, it is necessary to explore the main components of MBZ-YYH and unravel the potential mechanism in RA based on network pharmacology and molecular docking methods. Components and targets of MBZ-YYH were retrieved from the TCMSP. Relevant targets of RA were searched in GeneCards, therapeutic target database (TTD), and DisGeNET databases; the common targets of the MBZ-YYH compounds and RA were obtained by comparison; and a component-target interaction network was established by Cytoscape 3.9.1. Gene ontology (GO) analysis and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis were performed through the David database. Molecular docking was performed by PyMoL2.3.0 and AutoDock Vina1.1.2 software. 7 active ingredients and 58 putatively identified target genes were screened from MBZ, and 16 effective components of YYH and 230 potential targets were identified. There were 29 mutual targets between the two herbs and RA. Through the PPI network, 9 hub targets which contain JUN, CASP3, PPARG, PTGS2, GSK3B, CASP8, HMOX1, ICAM1, and HK2 were screened out. GO term enrichment analysis indicated that positive regulation of the apoptotic process, response to drugs, and response to hypoxia were significantly enriched. Based on KEGG analysis, it was mainly associated with the IL-17 signaling pathway, the TNF signaling pathway, and the p53 signaling pathway. The docking analysis revealed that the effective components showed strong binding activity with the receptors. The effects of the MBZ-YYH herb pair on RA were coordinated by the interaction of diverse components, which may be through the IL-17 signaling pathway and the TNF signaling pathway, which target GSK3B, HK2, caspase 3, and caspase 8, inhibiting the proliferation and glycolysis of rheumatoid arthritis fibroblast-like synovial cells (RA-FLS) and tending towards an increasing efficacy and decreasing toxicity effect on RA.

A Network Pharmacology Method Combined with Molecular Docking Verification to Explore the Therapeutic Mechanisms Underlying Simiao Pill Herbal Medicine against Hyperuricemia.

Hyperuricemia (HUA) is a common metabolic disease caused by disordered purine metabolism. We aim to reveal the mechanisms underlying the anti-HUA function of Simiao pill and provide therapeutic targets. Simiao pill-related targets were obtained using Herbal Ingredients' Targets (HIT), Traditional Chinese Medicine Systems Pharmacology (TCMSP), and Traditional Chinese Medicine Integrated Database (TCMID). HUA-associated targets were retrieved from GeneCards, DisGeNET, and Therapeutic Targets Database (TTD). Protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, ggraph and igraph R packages. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using ClusterProfiler. The top 10 core targets were identified through cytoHubba. Molecular docking was conducted using PyMOL and AutoDock high-performance liquid chromatograph (HPLC) analysis was performed to identify effective compounds of Simiao pill. Simiao pill-HUA target network contained 80 targets. The key targets were mainly involved in inflammatory responses. Insulin (INS), tumor necrosis factor (TNF), interleukin-6 (IL6), interleukin 1 beta (IL1B), vascular endothelial growth factor A (VEGFA), leptin (LEP), signal transducer and activator of transcription 3 (STAT3), C-C motif chemokine ligand 2 (CCL2), interleukin-10 (IL10), and toll like receptor 4 (TLR4) were the top 10 targets in the PPI network. GO analysis demonstrated the main implication of the targets in molecular responses, production, and metabolism. KEGG analysis revealed that Simiao pill might mitigate HUA through advanced glycation end-product- (AGE-) receptor for AGE- (RAGE-) and hypoxia-inducible factor-1- (HIF-1-) associated pathways. IL1B, IL6, IL10, TLR4, and TNF were finally determined as the promising targets of Simiao pill treating HUA. Through molecular docking and HPLC analysis, luteolin, quercetin, rutaecarpine, baicalin, and atractylenolide I were the main active compounds. Simiao pill can mitigate HUA by restraining inflammation, mediating AGE-RAGE- and HIF-1-related pathways, and targeting IL1B, IL6, IL10, TLR4, and TNF.

Elucidation of the mechanism of Gualou-Xiebai-Banxia decoction for the treatment of unstable angina based on network pharmacology and molecular docking

Objective: The aim of this study was to identify the potential pharmacological mechanisms of Gualou-Xiebai-Banxia decoction (GLXBBX) against unstable angina (UA). Materials and Methods: The active compounds of GLXBBX were collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and their targets were predicted using the SwissTargetPrediction database. The targets associated with UA were obtained from the Online Mendelian Inheritance in Man, GeneCards, and Therapeutic Target Database. Individual targets associated with UA and GLXBBX were cross-checked to identify the targets of GLXBBX involved in the treatment of UA. A protein–protein interaction network was built using the STRING online database. Cytoscape 3.7.2 software was used to screen out hub genes. Additional gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed using the clusterProfiler package in R. Results: A total of 28 bioactive compounds and 320 protein targets of GLXBBX associated with UA were screened out. Enrichment analysis indicated that the therapeutic effect of GLXBBX may be mediated through the PI3K/AKT, MAPK, and HIF-1 signaling pathways. Molecular docking suggested that the active compounds including Vitamin E, cavidine, and baicalein can bind to their protein receptors. Conclusions: This research confirmed the multifactorial effects of GLXBBX in the treatment of UA and laid the foundation for the experimental research on GLXBBX.

To Explore the Mechanism of Hawthorn in the Intervention of Hyperlipidemia Based on the Gene Expression Omnibus and Network Pharmacology

A common clinical treatment for hyperlipidemia in China is hawthorn, a traditional Chinese herb. However, few researches have been done on its active ingredients and their possible mechanisms for treating hyperlipidemia. The active chemical constituents of hawthorn were obtained from the encyclopedia of traditional Chinese medicine, the bioavailability and druglikeness properties of each active ingredient of hawthorn were analyzed using SwissADME and their possible targets of action were predicted using SwissTargetPrediction and PharmMapper. Then, we used the Gene Expression Omnibus-related gene microarray data to mine the differentially expressed genes for hyperlipidemia. Meanwhile, we collected relevant targets of hyperlipidemia through the DrugBank, Online Mendelian Inheritance in Man, GeneCards, DisGeNET and Therapeutic Target Database. Based on this data, a component-target-disease pathway and a protein-protein interaction networks were constructed using search tool for the retrieval of interacting genes/proteins. Finally, Metascape was systematically used to analyze the targets of hawthorn intervention in hyperlipidemia. A total of 8 active components and 312 hawthorn targets were gathered and 343 prospective targets associated with hyperlipidemia were predicted, 25 of which shared targets with hawthorn-related targets. Gene ontology enrichment analysis revealed that the mechanism of action of hawthorn in intervention of hyperlipidemia lies in the regulation of lipid metabolism, nutrition level, hormone level and cholesterol transport process. The Kyoto encyclopedia of genes and genomes enrichment analysis revealed that the peroxisome proliferator activated receptor signaling pathway contained the majority of the core targets. Molecular docking verified that hawthorn could bind closely to the core targets. According to the findings of network pharmacology and enrichment analysis, we predicted that the main active components of hawthorn to intervene in hyperlipidemia are epicatechin, officinalic acid and quercetin, which mainly intervene in hyperlipidemia through the peroxisome proliferator activated receptor signaling pathway.

Mechanism of ShuiJingDan in Treating Acute Gouty Arthritis Flares Based on Network Pharmacology and Molecular Docking.

This study examined the underlying mechanisms of SJD's anti-inflammatory and analgesic effects on acute GA flares. This study used pharmacology network and molecular docking methods. The active ingredients of ShuiJingDan (SJD) were obtained from the Traditional Chinese Medicine Systems Pharmacology Analysis Platform (TCMSP), and the relevant targets of GA were obtained from the Online Mendelian Inheritance in Man (OMIM) database and Therapeutic Target Database (TTD). The core drug group-target-disease Venn diagram was formed by crossing the active ingredients of SJD and the relevant targets. Gene Ontology (GO) analysis was conducted for functional annotation, DAVID was used for Kyoto Encyclopedia of Genes, and Genomes pathway enrichment analysis, and R was used to find the core targets. The accuracy of SJD network pharmacology analysis in GA treatment was verified by molecular docking simulations. Finally, a rat GA model was used to further verify the anti-inflammatory mechanism of SJD in the treatment of GA. SJD mainly acted on target genes including IL1B, PTGS2, CXCL8, EGF, and JUN, as well as signal pathways including NF-κB, Toll-like receptor (TLR), IL-17, and MAPK. The rat experiments showed that SJD could significantly relieve ankle swelling, reduce the local skin temperature, and increased the paw withdrawal threshold. SJD could also reduce synovial inflammation, reduced the concentrations of interleukin-1β (IL-1β), IL-8, and COX-2 in the synovial fluid, and suppressed the expression of IL1B, CXCL8, and PTGS2 mRNA in the synovial tissue. SJD has a good anti-inflammatory effect to treat GA attacks, by acting on target genes such as IL-1β, PTGS2, and CXCL8.

The mechanism of Bai He Gu Jin Tang against non-small cell lung cancer revealed by network pharmacology and molecular docking

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related burden and deaths, thus effective treatment strategies with lower side effects for NSCLC are urgently needed. To systematically analyze the mechanism of Bai He Gu Jin Tang (BHGJT) against NSCLC by network pharmacology and molecular docking. The active compounds of BHGJT were obtained by searching the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine and Encyclopaedia of Traditional Chinese Medicine. Search tool for interactions of chemicals was used for acquiring the targets of BHGJT. The component-target network was mapped by Cytoscape. NSCLC-related genes were obtained by searching Genecards, DrugBank and Therapeutic Target Database. The protein-protein interaction network of intersection targets was established based on Search Tool for Recurring Instances of Neighboring Genes (STRING), and further, the therapeutic core targets were selected by topological parameters. The hub targets were transmitted to Database for Annotation, Visualization and Integrated Discovery for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Finally, AutoDock Vina and MglTools were employed for molecular docking validation. Two hundred fifty-six compounds and 237 putative targets of BHGJT-related active compounds as well as 1721potential targets of NSCLC were retrieved. Network analysis showed that 8 active compounds of BHGJT including kaempferol, quercetin, luteolin, isorhamnetin, beta-sitosterol, stigmasterol, mairin and liquiritigenin as well as 15 hub targets such as AKR1B10 and AKR1C2 contribute to the treatment of BHGJT against NSCLC. GO functional enrichment analysis shows that BHGJT could regulate many biological processes, such as apoptotic process. Three modules of the endocrine related pathways including the inflammation, hypoxia related pathways as well as the other cancer related pathways based on Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis might explain the biological mechanisms of BHGJT in treating BHGJT. The results of molecular docking verified that AKR1B10 and AKR1C2 had the strongest binding activity with the 8 key compounds of NSCLC. Our study reveals the mechanism of BHGJT in treating NSCLC involving multiple components, multiple targets and multiple pathways. The present study laid an initial foundation for the subsequent research and clinical application of BHGJT and its active compounds against NSCLC.

Analyzing network pharmacology and molecular docking to clarify Duhuo Jisheng decoction potential mechanism of osteoarthritis mitigation

As a classic remedy for treating Osteoarthritis (OA), Duhuo Jisheng decoction has successfully treated countless patients. Nevertheless, its specific mechanism is unknown. This study explored the active constituents of Duhuo Jisheng decoction and the potential molecular mechanisms for treating OA using a Network Pharmacology approaches. Screening active components and corresponding targets of Duhuo parasite decoction by traditional Chinese medicine systems pharmacology database and analysis platform database. Combining the following databases yielded OA disease targets: GeneCards, DrugBank, PharmGkb, Online Mendelian Inheritance in Man, and therapeutic target database. The interaction analysis of the herb-active ingredient-core target network and protein-protein interaction protein network was constructed by STRING platform and Cytoscape software. Gene ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were carried out. PyMOL and other software were used to verify the molecular docking between the essential active components and the core target. 262 active ingredients were screened, and their main components were quercetin, kaempferol, wogonin, baicalein, and beta-carotene. 108 intersection targets of disease and drug were identified, and their main components were RELA, FOS, STAT3, MAPK14, MAPK1, JUN, and ESR1. Gene ontology analysis showed that the key targets were mainly involved in biological processes such as response to lipopolysaccharide, response to xenobiotic stimulus, and response to nutrient levels. The results of Kyoto Encyclopedia of Genes and Genomes analysis show that the signal pathways include the AGE - RAGE signaling pathway, IL - 17 signaling pathway, TNF signaling pathway, and Toll - like receptor signaling pathway. Molecular docking showed that the main active components of Duhuo parasitic decoction had a good bonding activity with the key targets in treating OA. Duhuo Jisheng decoction can reduce the immune-inflammatory reaction, inhibit apoptosis of chondrocytes, strengthen proliferation and repair of chondrocytes and reduce the inflammatory response in a multi-component-multi-target-multi-pathway way to play a role in the treatment of OA.

Uncovering the molecular mechanism of Gynostemma pentaphyllum (Thunb.) Makino against breast cancer using network pharmacology and molecular docking.

Because of their strong anti-cancer efficacy with fewer side effects, traditional Chinese medicines (TCM) have attracted considerable attention for their potential application in treating breast cancer (BC). However, knowledge about the underlying systematic mechanisms is scarce. Gynostemma pentaphyllum (Thunb.) Makino (GP), a creeping herb, has been regularly used as a TCM to prevent and treat tumors including BC. Again, mechanisms underlying its anti-BC properties have remained elusive. We used network pharmacology and molecular docking to explore the mechanistic details of GP against BC. The TCM systems pharmacology database and analysis platform and PharmMapper Server database were used to retrieve the chemical constituents and potential targets in GP. In addition, targets related to BC were identified using DrugBank and Therapeutic Target Database. Protein-protein interaction network, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of crucial targets were performed using the Search Tool for the Retrieval of Interacting Genes/Proteins and database for annotation, visualization, and integrated discovery databases, whereas the network visualization analysis was performed using Cytoscape 3.8.2. In addition, the molecular docking technique was used to validate network pharmacology-based predictions. A comparison of the predicted targets of GP with those of BC-related drugs revealed 26 potential key targets related to the treatment of BC, among which ALB, EGFR, ESR1, AR, PGR, and HSP90AA1 were considered the major potential targets. Finally, network pharmacology-based prediction results were preliminarily verified by molecular docking experiments. In addition, chemical constituents and potential target proteins were scored, followed by a comparison with the ligands of the protein. We provide a network of pharmacology-based molecular mechanistic insights on the therapeutic action of GP against BC. We believe that our data will serve as a basis to conduct future studies and promote the clinical applications of GP.

Mechanisms of Semen Cassiae to Treat Hypercholesterolemia Based on Molecular Docking

Hypercholesterolemia is a major risk factor of cardiovascular disease with high prevalence rate. Studies have shown that the traditional Chinese medicine: Semen Cassiae can reduce blood cholesterol and lipids, but the functional components and molecular mechanisms need further elucidation. In this study, molecular docking technology is used to explore the mechanism of Semen Cassiae in the treatment of hypercholesterolemia. A total 88 active ingredients and 196 isomers of Semen Cassiae were obtained from the traditional Chinese medicine database: HERB. 6 hypercholesterolemia-related drug targets: proprotein convertase subtilisin/kexin type 9 (PCSK9), thyroid Hormone Receptor β (THRB), peroxisome proliferator-activated receptors (PPARd), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), insulin receptor (IR) and squalene monooxygenase (SQLE) were obtained from the Therapeutic Target Database. After data preprocessing, molecular docking analysis was conducted using the LibDock tool in Discovery Studio software, and the main “active ingredient-target” combinations with high scores were screened. The structure results showed high binding affinity of the active ingredients to the hypercholesterolemia-related targets. Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed the involved pathways, including cholesterol and lipid metabolism, lipoprotein particle formation, cholesterol and lipid transfer and lipoprotein particle receptor binding processes. This study revealed that the anti-hypercholesterolemia activity of Semen Cassiae is a multicomponent, multitarget, and multipathway effects, and provides evidence for further development the clinical application value of Semen Cassiae on hypercholesterolemia.

Exploring the mechanisms underlying the therapeutic effect of the drug pair Rhubarb-Coptis in diabetic nephropathy using network pharmacology and molecular docking analysis.

To use network pharmacology to explore the mechanism of the drug pair Rhubarb-Coptis in the treatment of diabetic nephropathy (DN). The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen active ingredients of drug pair Rhubarb-Coptis. Targets were obtained using the TCMSP and SwissTargetPrediction databases. DN disease targets were extracted from the Online Mendelian Inheritance in Man (OMIM), GeneCards, and Therapeutic Target database (TTD) databases. A "drug-compound-target" network and protein-protein interaction (PPI) network were constructed and analyzed through the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and Cytoscape software. Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed in the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database. Molecular docking was performed using AutoDock Vina and PyMOL software. A total of 30 active components and 609 targets of Rhubarb-Coptis were screened out, and 98 common targets of DN and Rhubarb-Coptis were obtained. Quercetin, berberine, epiruberine, epautin, and moupinamide were the main active components in the treatment of DN. The STAT3, CTNNB1, PIK3R1, PIK3CA, and TP53 genes were identified as the potential 5 key targets. The GO enrichment analysis showed that these 5 key targets mainly involved in inflammation, oxidative stress, and apoptosis. KEGG enrichment analysis showed that the pathways were mainly enriched in the AGE-RAGE and HIF-1 signaling pathways. Molecular docking revealed that the 5 key targets could combine well with their corresponding active compounds. This study expounds the therapeutic effect of Rhubarb-Coptis on DN from a holistic perspective, and provides a valuable basis for clinical application and academic research.

Pharmacodynamic mechanism of Tibetan medicine Liurui Capsules on experimental autoimmune uveitis in rats based on network pharmacology and animal experiments

By integrating network pharmacology and animal experiments, we studied the pharmacodynamic mechanism of the Tibetan medicine Liurui Capsules in the treatment of experimental autoimmune uveitis(EAU). The active ingredients and targets of Liurui Capsules were searched against the Encyclopedia of Traditional Chinese Medicine(ETCM), Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine(BATMAN-TCM), and relevant literatures. The EAU-related targets were obtained from Gene Expression Omnibus(GEO), GeneCards, Online Mendelian Inheritance in Man(OMIM), and Therapeutic Target Database(TTD). The common targets shared by Liurui Capsules and EAU were identified, and the protein-protein interaction(PPI) network was established via STRING. Gene Ontology(GO) annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were conducted via g: Profiler. The rat model of EAU was induced by interphotoreceptor retinoid-binding protein(IRBP) and treated with Liurui Capsules. The inflammatory response of anterior segment and the pathological morphology of retina were observed. The mRNA and protein levels of delta-like ligand 4(DLL4), Notch1, interleukin-17(IL-17), and tumor necrosis factor-alpha(TNF-α) were determined by real-time quantitative PCR(q-PCR) and Western blot, respectively. The network pharmacology analysis predicted 51 common targets of Liurui Capsules and EAU, which were mainly involved in IL-17, TNF, and nuclear factor-kappa B(NF-κB) signaling pathways, as well as liposome receptors and other biological processes. Compared with the control group, the modeling of EAU caused inflammatory changes in the anterior segment and retina and up-regulated mRNA and protein levels of DLL4, Notch1, IL-17, and TNF-α in ocular tissue. Compared with the model group, Liurui Capsules reduced the inflammatory reaction of anterior segment and retina and down-regulated the mRNA and protein levels of DLL4, Notch1, IL-17, and TNF-α. Liurui Capsules can down-regulate the expression of the proteins involved in DLL4/Notch1/IL-17 signaling pathway in ocular tissue and alleviate the ocular inflammation, which may be one of the mechanisms of Liurui Capsules in the treatment of EAU.

Detecting potential mechanism of vitamin D in treating rheumatoid arthritis based on network pharmacology and molecular docking.

Aim: Vitamin D plays a vital role in Rheumatoid arthritis (RA). However, the mechanism of vitamin D and rheumatism is still unclear. Therefore, a strategy based on network pharmacology and molecular docking was used to explore the mechanism of vitamin D and RA. Methods: The targets of RA were obtained from the GeneCards database and Therapeutic Targets Database, and the targets of vitamin D were obtained from the Drugbank database and STITCH database. Next, overlapping genes were identified by Venny, and further Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and molecular docking analyses were performed. Results: A total of 1,139 targets of RA and 201 targets of vitamin D were obtained. A total of 76 overlapping genes were identified by Venny. The enrichment analysis showed that cell proliferation, immune response, and apoptotic process were the critical biological processes of vitamin D in treating RA. Antifolate resistance, osteoclast differentiation, and the nuclear factor-kappa B (NF-κB) signalling pathway are fundamental mechanisms of vitamin D in treating RA. According to further molecular docking, ALB, TNF, CASP3, and TP53 may be important punctuation points or diagnostic markers for future RA treatment. Conclusion: By analysing overlapping genes of diseases and drugs, this study confirmed that ALB, TNF, CASP3, and TP53 may be essential markers or diagnostic markers for future RA treatment.

Exploring the mechanism of Epimedii folium and notoginseng radix against vascular dementia based on network pharmacology and molecular docking analysis: pharmacological mechanisms of EH-PN for VD.

To explore the mechanism of Epimedii Folium (HF) and Notoginseng Radix (NR) intervention in vascular dementia (VD). This study used the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database to collect the active ingredients and potential drug targets of HF and NR, the Uniprot database to convert drug target names into gene names, GeneCards, Drugbank, Therapeutic Target Database, and Online Mendelian Inheritance in Man database to collect the potential disease targets of VD, and then combined them with the drug targets to construct the HF-NR-VD protein-protein interaction (PPI) network by Search Tool for the Retrieval of Interacting (STRING). Cytoscape (version 3.7.1) was used to perform cluster analysis of the PPI network. Metascape database was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The potential interaction of the main components of the HF-NR couplet medicine with core disease targets was revealed by molecular docking simulations. There were 23 predicted active ingredients in HF and NR, and 109 common drug targets that may be involved in the treatment of VD. Through PPI network analysis, 30 proteins were identified as core proteins owing to their topological importance. GO functional analysis revealed that the primary biological processes were mainly related to inflammation, apoptosis, and the response to oxidative stress. KEGG pathway enrichment analysis revealed that TNF and PI3K/Akt signaling pathways may occupy the core status in the anti-VD system. Molecular docking results confirmed that the core targets of VD had a high affinity for the main compounds of the HF-NR couplet medicine. We demonstrated the multi-component, multi-target, and multi-pathway characteristics of HF-NR couplet medicine for the treatment of VD and provided a foundation for further clinical application and experimental research.

Mechanism of Epimedium intervention in heart failure based on network pharmacology and molecular docking technology.

To analyze the pharmacological mechanism of Epimedium in regulating heart failure (HF) based on the network pharmacology method, and to provide a reference for the clinical application of Epimedium in treating HF. Obtaining the main active ingredients and their targets of Epimedium through TCMSP (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform) database. Access to major HF targets through Genecards, OMIM, PharmGKB, Therapeutic Target Database, Drug Bank database. Protein interaction analysis using String platform and construction of PPI network. Subsequently, Cytoscape software was used to construct the "Epimedium active ingredient-heart failure target" network. Finally, the molecular docking is verified through the Systems Dock Web Site. The core active ingredients of Epimedium to regulate HF are quercetin, luteolin, kaempferol, etc. The core targets are JUN, MYC, TP53, HIF1A, ESR1, RELA, MAPK1, etc. Molecular docking validation showed better binding activity of the major targets of HF to the core components of Epimedium. The biological pathways that Epimedium regulates HF mainly act on lipid and atherosclerotic pathways, PI3K-Akt signaling pathway, and chemoattractant-receptor activation. And its molecular functions are mainly DNA-binding transcription factor binding, RNA polymerase II-specific DNA-binding transcription factor binding, and neurotransmitter receptor activity. This study reveals the multi-component, multi-target and multi-pathway mechanism of action of Epimedium in regulating mental failure, and provides a basis for the clinical development and utilization of Epimedium to intervene in HF.

Network pharmacology and molecular docking-based analysis of protective mechanism of MLIF in ischemic stroke.

This study aimed to evaluate the potential mechanism by which Monocyte locomotion inhibitory factor (MLIF) improves the outcome of ischemic stroke (IS) inflammatory injury. Potential MLIF-related targets were predicted using Swiss TargetPrediction and PharmMapper, while IS-related targets were found from GeneCards, PharmGKB, and Therapeutic Target Database (TTD). After obtaining the intersection from these two datasets, the Search Tool for Retrieval of Interacting Genes/Protein (STRING11.0) database was used to analyze the protein-protein interaction (PPI) network of the intersection and candidate genes for MLIF treatment of IS. The candidate genes were imported into the Metascape database for Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The top 20 core genes and the "MLIF-target-pathway" network were mapped using the Cytoscape3.9.1. Using AutoDock Vina1.1.2, the molecular docking validation of the hub targets and MLIF was carried out. In the experimental part, transient middle cerebral artery occlusion (tMCAO) and oxygen and glucose deprivation (OGD) models were used to evaluate the protective efficacy of MLIF and the expression of inflammatory cytokines and the putative targets. MLIF was expected to have an effect on 370 targets. When these targets were intersected with 1,289 targets for ischemic stroke, 119 candidate therapeutic targets were found. The key enriched pathways were PI3K-Akt signaling pathway and MAPK signaling pathway, etc. The GO analysis yielded 1,677 GO entries (P < 0.01), such as hormone stimulation, inflammatory response, etc. The top 20 core genes included AKT1, EGFR, IGF1, MAPK1, MAPK10, MAPK14, etc. The result of molecular docking demonstrated that MLIF had the strong binding capability to JNK (MAPK10). The in vitro and in vivo studies also confirmed that MLIF protected against IS by lowering JNK (MAPK10) and AP-1 levels and decreasing pro-inflammatory cytokines (IL-1, IL-6). MLIF may exert a cerebral protective effect by inhibiting the inflammatory response through suppressing the JNK/AP-1 signaling pathway.

Exploration of potential targets and mechanisms of Naringenin in treating autism spectrum disorder via network pharmacology and molecular docking.

Naringenin (NR) is a kind of flavonoid which plays a great role in the treatment of autism spectrum disorder (ASD). However, the underlying mechanism of NR in treating ASD still remains unclear. This study used network pharmacology and molecular docking to examine the potential targets and pharmacological mechanism of NR on ASD. Targets related to NR were screened from Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), Encyclopedia of Traditional Chinese Medicine Database (ETCM), Traditional Chinese Medicine Integrated Database (TCMID), PharmaMapper database, and targets related to ASD were screened from Online Mendelian Inheritance In Man (OMIM), Disgenet, GeneCards, Therapeutic Target Database (TTD), Drugbank, and ETCM. Screened of the intersected gene targets. Then, we used the protein-protein interaction (PPI) networks to construct a PPI network and used Network Analyzer plug-in to perform topological analysis to screen out the core target. We used Metascape platform to perform gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and used Chem draw, Pymol, AutoDock 1.5.6 software for molecular docking verification with core targets. A total of 149 targets of NR and 1594 potential targets of ASD were screened, and 43 intersected targets and 8 key targets were obtained and screened. A total of 176 GO items were obtained by GO enrichment analysis (P < .05), 153 entries on biological process (BP), 12 entries on BP and 11entries on cell composition (CC) were included. A total of 100 signaling pathways were obtained by KEGG pathway enrichment screening (P < .05).The pathways that are closely related to the pathogenesis of ASD are estrogen signaling, thyroid hormone signaling pathway, prolactin signaling pathway, and endocrine resistance pathway. Molecular docking results showed that NR had the best docking activity with the core target CASP3, and had good binding ability with AKT1, ESR1, ACTB and MAPK3. Taken together, our findings support that NR exerts therapeutic effects on ASD with multi-target, and multi-pathway characteristics, which provides a preliminary theoretical basis for clinical trials. The mechanism of anti-oxidative stress response, anti-apoptosis, regulation of cell growth and metabolism, anti-inflammatory, balance hormone levels may be important for the therapeutic effect.

Exploration of the Pharmacological Mechanism of Bufei Nashen Pill in Treating Chronic Obstructive Pulmonary Disease Using Network Pharmacology Integrated Molecular Docking

Objective: Based on network pharmacological analysis and molecular docking verification, the therapeutic mechanism of Bufei Nashen Pill (BFNSP) in treating chronic obstructive pulmonary disease (COPD) is discussed. Methods: First, the active ingredients and therapeutic targets of BFNSP were determined based on literature and the Chinese medicine system pharmacology database. Relevant targets of COPD were determined using GeneCard, Therapeutic Target Database and Online Mendelian Inheritance in Man (OMIM). The con-targets of BFNSP and COPD were then obtained through the Veen platform, which were implemented in Cytoscape to build “Drug-Ingredients-Potential Target network.” Target gene function enrichment analysis and signal pathway analysis were performed based on STRING database, Database for Annotation, Visualization, and Integrated Discovery, and Kyoto Encyclopedia of Genes and Genomes Pathway database. Finally, SYBYL 2.2.1 software was used to finish docking. Results: In the Drug-Ingredients-Potential Targets network, 172 active ingredients and 183 potential targets were found. Enrichment analysis showed that potential targets mainly involve biological functions such as inflammation, reactive oxygen, and immunity. Molecular docking showed that the active ingredients of BFNSP had preferential interaction with interleukin 6, mitogen-activated protein kinase 1, SRC, epidermal growth factor receptor, and matrix metalloproteinase-9. Conclusion: BFNSP can be used to treat COPD by the regulation of inflammation, immunity, and hypoxia tolerance.

Combining Network-based and Matrix Factorization to Predict Novel Drug-target Interactions: A Case Study Using the Brazilian Natural Chemical Database

Background: Chemogenomic techniques use mathematical calculations to predict new DrugTarget Interactions (DTIs) based on drugs' chemical and biological information and pharmacological targets. Compared to other structure-based computational methods, they are faster and less expensive. Network analysis and matrix factorization are two practical chemogenomic approaches for predicting DTIs from many drugs and targets. However, despite the extensive literature introducing various chemogenomic techniques and methodologies, there is no consensus for predicting interactions using a drug or a target, a set of drugs, and a dataset of known interactions Methods: This study predicted novel DTIs from a limited collection of drugs using a heterogeneous ensemble based on network and matrix factorization techniques. We examined three network-based approaches and two matrix factorization-based methods on benchmark datasets. Then, we used one network approach and one matrix factorization technique on a small collection of Brazilian plant-derived pharmaceuticals. Results: We have discovered two novel DTIs and compared them to the Therapeutic Target Database to detect linked disorders, such as breast cancer, prostate cancer, and Cushing syndrome, with two drugs (Quercetin and Luteolin) originating from Brazilian plants. Conclusion: The suggested approach allows assessing the performance of approaches only based on their sensitivity, independent of their unfavorable interactions. Findings imply that integrating network and matrix factorization results might be a helpful technique in bioinformatics investigations involving the development of novel medicines from a limited range of drugs.

Mechanisms of action of Zishen Yutai pills in treating premature ovarian failure determined by integrating UHPLC-Q-TOF-MS and network pharmacology analysis

BackgroundZishen Yutai (ZSYT) pill, a patent Chinese medicine, has been widely used in the treatment of infertility, abortion, and adjunctive treatment of in vitro fertilization (IVF) for decades. Recently, the results of clinical observations showed that premature ovarian failure (POF) patients exhibited improved expression of steroids and clinical symptoms associated with hormone disorders after treatment with Zishen Yutai pills. However, the pharmacological mechanism of action of these pills remains unclear.MethodsThe compounds of Zishen Yutai pills found in blood circulation were identified via ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) technique in the serum of POF mice after oral administration of Zishen Yutai pills. The potential targets of compounds were screened using Traditional Chinese Medicine Systems Pharmacology Database, Traditional Chinese Medicine Database@Taiwan, Drugbank Database, PubChem, HIT, Pharmapper, and Swiss Target Prediction. The target genes associated with POF were collected from Online Mendelian Inheritance in Man Database, PharmGkb, Genecards, Therapeutic Target Database, and Genetic Association Database. The overlapping genes between the potential targets of Zishen Yutai pills’ compounds and the target genes associated with POF were clarified via protein-protein interaction (PPI), pathway, and network analysis.ResultsNineteen compounds in Zishen Yutai pills were detected in the serum of POF mice after oral administration. A total of 695 Zishen Yutai (ZSYT) pill-related targets were screened, and 344 POF-related targets were collected. From the results of Zishen Yutai (ZSYT) pill-POF PPI analysis, CYP19A1, AKR1C3, ESR1, AR, and SRD5A2 were identified as key targets via network analysis, indicating their core role in the treatment of POF with Zishen Yutai pills. Moreover, the pathway enrichment results suggested that Zishen Yutai pills treated POF primarily by regulating neuroactive ligand-receptor interaction, steroid hormone biosynthesis, and ovarian steroidogenesis.ConclusionsVia virtual screening, we found that regulation of neuroactive ligand-receptor interaction, steroid hormone biosynthesis, and ovarian steroidogenesis was the potential therapeutic mechanism of Zishen Yutai pills in treating POF. Our study suggested that combining the analysis of Zishen Yutai pills’ compounds in blood in vivo in the POF model and network pharmacology prediction might offer a tool to characterize the mechanism of Zishen Yutai pills in the POF.