Network Pharmacology-based Systematic Analysis of Molecular Mechanisms of Dingji Fumai Decoction for Ventricular Arrhythmia

Liang, Yi; Liang, Baoyu; Rui, Wen; Chen, Wen; Zhao, Lizhi

doi:10.21203/rs.3.rs-117498/v1

Cited by 5 publications

(7 citation statements)

References 46 publications

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“…Moreover, positive cells were bigger and rounded with cytoplasmic vacuolization. These results indicated that R1D2-10 treatment led to senescence entrance triggered by telomere shortening; this was comparable with the effect of other reported telomerase inhibitors (59)(60)(61)(62)(63)(64)(65).…”

Section: Hdkc1 Residue Interactionsupporting

confidence: 87%

“…All analogs complied with Lipinski's rule of five, which indicates a good druggability profile, and most showed suitable values of ADME properties using the pkCSM prediction tool, which is broadly reported (22,(76)(77)(78). Additionally, target prediction of small bioactive molecules was analyzed using Swiss Target Prediction (63,79). Small molecules are designed to bind to proteins or other macro-molecular targets to modulate their activity, resulting in phenotypic effects.…”

Section: Hdkc1 Residue Interactionmentioning

confidence: 99%

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In vitro characterization and rational analog design of a novel inhibitor of telomerase assembly in MDA MB 231 breast cancer cell line

et al. 2022

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Tumor cells have unlimited replicative potential, principally due to telomerase activity, which requires assembly of components such as dyskerin (hDKC1), human telomerase reverse transcriptase and human telomerase RNA (hTR). The present study aimed to develop novel inhibitors of telomerase to target the interaction between hTR and hDKC1. Based on docking-based virtual screening, the candidates R1D2-10 and R1D2-15, which exert an in vitro inhibitory effect on telomerase activity, were selected. Human mammary adenocarcinoma MDA-MB 231 cell line was selected to evaluate the treatment with the aforementioned compounds; the effect on telomere length was evaluated by qPCR, where both compounds caused telomere shortening. Furthermore, expression of genes related to apoptosis and senescence process, as well SA β galactosidase staining and caspase 3 activity. We determine that only compound R1D2-10 showed and effect on the induction of these cellular processes. To identify a lead compound from R1D2-10, 100 analogs were designed by LigDream server and then analyzed by AutoDock Vina and Protein-Ligand Interaction Profile to calculate their docking energy and target interaction. Those with the best values and specific residue interactions were selected for in silico prediction of absorption, distribution, metabolism, excretion (ADME), off-target interaction, toxicity and chemical diversity. A total of nine chemically different analogs was identified with higher docking affinity to the target, suitable ADME properties and not off-target interaction and side effects. These results indicated R1D2-10 and its analogs may serve as potential novel inhibitors of telomerase and antitumoral drugs in clinical use.

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Section: Hdkc1 Residue Interactionsupporting

confidence: 87%

Section: Hdkc1 Residue Interactionmentioning

confidence: 99%

In vitro characterization and rational analog design of a novel inhibitor of telomerase assembly in MDA MB 231 breast cancer cell line

et al. 2022

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“…The binding activity is expressed as binding energy. The lower the binding energy, the more stable the docking module (30,31). In general, docking energy <-4.25 kcal/mol has docking activity, docking energy <-5 kcal/mol has good docking activity, while docking energy <-7 kcal/mol has very strong docking activity (32).…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, the active components and five core gene targets were matched and the docking potential was examined. The binding energy for all compounds and core genes was in the range of -8.2~-4.4 kcal/mol; the larger the absolute value of binding energy, the stronger the molecular docking effect (30,39). Only three core genes, STAT3, MPO and MMP9 had binding energy >-5 kcal/mol with active components of GEB and showed good docking activity (Table II).…”

Section: Construction and Analysis Of Herb-compound-targets-disease N...mentioning

confidence: 98%

Network pharmacology and molecular docking analysis on molecular targets and mechanisms of Gastrodia elata Blume in the treatment of ischemic stroke

et al. 2022

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Gastrodia elata Blume (GEB) is widely used to treat cardio-cerebrovascular disease in China and in traditional Chinese medicine it is considered to be a dispelling wind and dredging collateral. However, the mechanism and active components of the plant in treating ischemic stroke (IS) remain unclear. The present study aimed to identify the active components and mechanism of GEB in treating IS using network pharmacology and molecular docking technology. Network analysis predicted 752 potential targets from 14 compounds in GEB, sharing 32 key targets with IS-associated targets. Gene Ontology analysis of key targets showed that 'oxidative stress', 'immune response' and 'regulation of blood circulation' were significantly enriched. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that the key targets regulated 11 representative pathways including 'arachidonic acid metabolism', 'lipid and galactose metabolism'. In the protein-protein interaction network, five core targets, including toll-like receptor agonist, STAT3, myeloperoxidase (MPO), prostaglandin-endoperoxide synthase and matrix metalloproteinase (MMP)9, were identified and successfully docked with four active components: Palmitic acid, alexandrin, para-hydroxybenzaldehyde and gastrodin. Alexandrin, para-hydroxybenzaldehyde, and gastrodin are closely related to brain ischemia/reperfusion damage and repair. Therefore, to further verify the mechanism of action of three active components in the second part, we established the HT22 oxygen-glucose deprivation-reperfusion (OGD/R) model. Cell Counting Kit-8 assay and western blot analysis demonstrated that these three active components of GEB regulated core targets of molecular docking, such as STAT3, MPO and MMP9. In vitro experiments showed that OGD/R decreased cell survival, while this effect was reversed by the three active components of GEB. In addition, western blot analysis indicated that alexandrin upregulated expression of phosphorylated-STAT3, para-hydroxybenzaldehyde downregulated MPO and gastrodin downregulated MMP9. Therefore, the present study showed that GEB may prevent and treat IS via interaction between the active components and the main targets, which is key for investigating the efficacy of traditional Chinese medicine.

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“…A Venn diagram was used to identify the screened targets that were shared by GD and DF. The common targets were considered the therapeutic targets of GD in the treatment of DF, as described previously (Liang et al 2021). The STRING database (https://cn.string-db.org/) was used to construct a target protein-protein interaction (PPI) network (Szklarczyk et al 2019).…”

Section: Construction Of the Intersection Network And Ppi Networkmentioning

confidence: 99%

Exploring the mechanism by which aqueous Gynura divaricata inhibits diabetic foot based on network pharmacology, molecular docking and experimental verification

Sun

Gao

Liu

et al. 2022

Preprint

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Background To predict and validate the potential mechanism by which Gynura divaricata (GD) functions in the treatment of diabetic foot (DF). Methods The main chemical constituents of GD were identified by reviewing the literature, the traditional Chinese medicine database platform (TCMIP) and the BATMAN-TCM platform. DF disease targets were identified with the GeneCards database, and the compound-target network was constructed by using the intersection of drugs and disease. The STRING platform was used to construct the protein–protein interaction (PPI) network, and Cytoscape 3.7.2 software was used to visualize the results. Moreover, the Metascape database was used for Gene Ontology (GO) enrichment analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking of the active ingredients of GD and core protein targets of DF was performed using AutoDock software. Finally, the predicted results were preliminarily verified with experiments. Results A total of 140 potential targets of GD were identified and associated with DF. According to the PPI network analysis, GD accelerated DF wound healing, and the mechanism may be related to proteins such as AKT1, TP53, IL6, CASP3, TNF, and VEGFA. GO and KEGG enrichment analyses indicated that GD may play a role in the treatment of diabetic foot by affecting various signaling pathways. Molecular docking results showed that the proteins AKT1, TP53, IL6, CASP3, TNF, and VEGFA were closely associated with the components of GD. The animal experiments showed that GD reduced the levels of IL-6 and TNF-α and increased the mRNA and protein expression of VEGFA in rats with DF. Conclusions GD regulates multiple targets and multiple pathways to promote wound healing in DF.

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Network Pharmacology-based Systematic Analysis of Molecular Mechanisms of Dingji Fumai Decoction for Ventricular Arrhythmia

Cited by 5 publications

References 46 publications

In vitro characterization and rational analog design of a novel inhibitor of telomerase assembly in MDA MB 231 breast cancer cell line

In vitro characterization and rational analog design of a novel inhibitor of telomerase assembly in MDA MB 231 breast cancer cell line

Network pharmacology and molecular docking analysis on molecular targets and mechanisms of Gastrodia elata Blume in the treatment of ischemic stroke

Exploring the mechanism by which aqueous Gynura divaricata inhibits diabetic foot based on network pharmacology, molecular docking and experimental verification

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