Molecular mechanism of Ferula asafoetida for the treatment of asthma: Network pharmacology and molecular docking approach

Asthma is a significant health-care burden that has great impact on the quality of life of patients and their families. The limited amount of previously reported data and complicated pathophysiology of asthma make it a difficult to treat and significant economic burden on public healthcare systems. Ferula asafoetida is an herbaceous, monoecious, perennial plant of the Umbelliferae family. In Asia, F. asafoetida is used to treat a range of diseases and disorders, including asthma. Several in vitro studies demonstrated the therapeutic efficacy of F. asafoetida against asthma. Nevertheless, the precise molecular mechanism is yet to be discovered. In the framework of current study, network pharmacology approach was used to identify the bioactive compounds of F. asafoetida in order to better understand its molecular mechanism for the treatment of asthma. In present work, we explored a compound-target-pathway network and discovered that assafoetidin, cynaroside, farnesiferol-B, farnesiferol-C, galbanic-acid, and luteolin significantly influenced the development of asthma by targeting MAPK3, AKT1 and TNF genes. Later, docking analysis revealed that active constituents of F. asafoetida bind stably with three target proteins and function as asthma repressor by regulating the expression of MAPK3, AKT1 and TNF genes. Thus, integration of network pharmacology with molecular docking revealed that F. asafoetida prevent asthma by modulating asthma-related signaling pathways. This study lays the basis for establishing the efficacy of multi-component, multi-target compound formulae, as well as investigating new therapeutic targets for asthma.     

Virtual screening of active compounds from Artemisia argyi and potential targets against gastric ulcer based on Network pharmacology

Artemisia argyi (AA) is one of the renowned herbs in China often used in the treatment of gastric ulcer (GU). Aiming to predict the active compounds and systematically investigate the mechanisms of Artemisia argyi for GU treatment, the approach of network pharmacology, molecular docking, gene ontology (GO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were adopted, respectively, in present study. A total of 13 predicted targets of the 103 compounds in Artemisia argyi were obtained. Sorted by pathogenic mechanisms of targets and structure types of compounds, it was revealed that flavonoids and sesquiterpenes had better performance than monoterpenes. The network analysis showed that Phospholipase a2 (PA21B), Sulfotransferase family cytosolic 2b member 1 (ST2B1), Nitric-oxide synthase, endothelial (NOS3), Gastrin (GAST), neutrophil collagenase (MMP-8), Leukotriene A-4 hydrolase (LKHA4), Urease maturation factor HypB (HYPB), and Periplasmic serine endoprotease DegP (HtrA) were the key targets with intensely interaction. The functional enrichment analysis indicated that AA probably produced the gastric mucosa protection effects by synergistically regulating many biological pathways, such as NF-κB signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, VEGF signaling pathway, and Toll-like receptor signaling pathway, etc. In addition, C73 and C15 might be promising leading compounds with good molecular docking score. As a consequence, this study holistically illuminates the active constituents and mechanisms based on data analysis, which contributes to searching for leading compounds and the development of new drugs for gastric ulcer.     

Molecular docking analysis of bioactive compounds from Plectranthus amboinicus with glucokinase

Natural remedies from medicinal plants are known to be effective and reliable appropriate medicine for illnesses. The current research examined Plectranthus amboinicus'' anti diabetic property by docking the bioactive compounds of certain target proteins. We document the molecular docking analysis of bioactive compounds from Plectranthus amboinicus with protein Glucokinase. Molecular docking experiments were carried out in PyRx software. Results of these docking experiments showed that most of the compounds showed very strong interaction with the target protein Glucokinase. Based on the scoring parameters we have selected best four compounds (Rutin, Salvianolic acid, Luteolin and Salvigenin) which showed very good docking score and hydrogen bond interaction for diabetics.     

Chemical constituents and synergistic anti-gout studies on Eurycoma longifolia and potential mechanisms evaluation based on systemic analysis approach

37 compounds mainly including triterpenoids with the quassinoid skeleton and β-carboline alkaloids have been isolated from the roots of Eurycoma longifolia Jack (EL), which has been used as traditional medicine for a long history. It has been demonstrated that the total extracts from EL could significantly inhibit the joint swelling in MSU-induced acute gout arthritis rat model at middle and high doses (P < 0.05, P < 0.01), as meanwhile, better performance than that of positive control (P < 0.05, P < 0.01) has been observed at the dose of 10 g/kg. Aiming to search potential compounds and probable mechanisms, network pharmacology, molecular docking and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were adopted, leading to the hypothesis of 17 targets related to different pathogenesis of gout and 5 potential compounds (C36, C107, C124, C125 and C130) among 156 selected compounds, playing synergetic role with multiple targets. Instead of the guiding ideology of “a gene, a drug, a disease”, varieties of compounds but not a single one from EL display holistic performance through multiple pathways with multi-targets. It was noteworthy that Xanthine dehydrogenase/oxidase (XDH), Prostaglandin G/H synthase 2 (PTGS2), Fatty acid-binding protein, liver (FABP1), Purine nucleoside phosphorylase (PNP), and Peroxisome proliferator activated receptor alpha (PPARA) were the key targets with intensely interaction. Furthermore, the functional enrichment analysis indicated that EL probably produced the gout protection effects by synergistic regulation in multiple biological pathways, including Toll-like receptor signaling pathway, MAPK signaling pathway, and NOD-like receptor signaling pathway, etc.     

In vitro and in silico elucidation of antidiabetic and anti-inflammatory activities of bioactive compounds from Momordica charantia L.

Bitter melon (Momordica charantia) has been used to manage diabetes and related conditions in various parts of the world. In the present study, ten compounds were isolated from acetone and methanol extracts of bitter melon. The chemical structures of compounds were unambiguously elucidated by 1D, 2D NMR, and high-resolution mass spectra. Identified compounds 1–7 exhibited significant inhibition of α-amylase and moderate inhibition of α-glucosidase activities. Momordicoside G and gentisic acid 5-O-β-d-xyloside showed the highest inhibition of α-amylase (70.5%), and α-glucosidase (56.4%), respectively. Furthermore, molecular docking studies of isolated compounds 1–7 were able to bind to the active sites of both enzymes. Additionally, the isolated compounds 1–7 significantly attenuated lipopolysaccharide (LPS)-induced inflammation, downregulating the expression of pro-inflammatory markers NF-κB, INOS, IL-6, IL-1β, TNF-α, and Cox-2 in murine macrophage RAW 264.7 cells. One phenolic derivative, gentisic acid 5-O-β-d-xyloside, was isolated and identified for the first time from bitter melon, and significantly suppressed the expression of Cox-2 and IL-6 compared to the LPS-treated group. α-Amylase and α-glucosidase are targets of anti-diabetes drugs, our findings suggest that compounds purified from bitter melon may have potential to use as functional food ingredients for the prevention of type 2 diabetes and related inflammatory conditions.     

Molecular docking analysis of bioactive compounds from Mollugo cerviana (L.) SER with DHFR for antifungal activity

Fungal infections have been increasing in recent years due to growing number of high-risk patients particularly immuno compromised hosts. Candida is the third- or fourth-most-common isolate in nosocomial bloodstream infections. The increase of fungal resistance to classical drugs, the treatment costs, and the fact that most available antifungal drugs have only fungistatic activity, justify the search for new strategies. Identification of therapeutic compounds from plants has been the centre of attraction ever since they were discovered. It is of interest to document the molecular docking analysis of bioactive compounds present in Mollugo cerviana (L.) SER with the DHFR protein target for antifungal activity. We show the optimal binding features of several compounds from the extract with in vivo and in vitro activities. Results of this showed that all compounds showed good antimicrobial activity and a very good antifungal activity against the target DHFR protein. So, these compounds may act as potential drug molecules after the experimental validation.     

Revealing synergistic mechanism of multiple components in Stauntonia brachyanthera Hand.-Mazz. for gout by virtual screening and system pharmacological approach

Stauntonia brachyanthera Hand.-Mazz. (SB), reported as a traditional Chinese medicine, displays a wide spectrum of interesting bioactivities, such as anti-inflammatory and analgesia. It is noteworthy that anti-gout effects of the components in SB have been reported. Hence, this study contributes to the prediction of promising active compounds and mechanisms for the treatment of gout. The active compounds with better oral bioavailability, and drug-likeness of SB were selected for further investigation by the approach of network pharmacology, molecular docking, gene ontology (GO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis, respectively. A total of 34 predicted targets and 98 compounds in SB were obtained. Sorted by structure types of compounds, phenylethanoid glycosides exhibited the best anti-gout activity, followed by phenolics and flavonoids. What’s more, it was shown in the network analysis that Serine/threonine-protein kinase mTOR (mTOR), Mitogen-activated protein kinase 12 (MAPK12), tumor necrosis factor (TNF-α), Integrin alpha-4 (ITGA4) and Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG) were the key targets with intensely interaction, which should be attached more attention for further study. The functional enrichment analysis indicated that SB probably produced the anti-gout effects by synergistically regulating many biological pathways, such as MAPK signaling pathway, PI3K-Akt signaling pathway, Toll-like receptor signaling pathway and NOD-like receptor signaling pathway, etc. In addition, C61, C67, C68 and C81 might be promising leading compounds with good molecular docking score. As a consequence, the active constituents and mechanisms based on data analysis were holistically illuminated, which was of vital importance to the development of new drugs for gout.     

基于疾病与活性化合物靶点网络构建的异鼠李素抗缺血性神经损伤作用评价与验证研究

基于网络药理学与分子对接探讨异鼠李素对缺血性神经损伤的治疗作用。采用ChEMBL、SwissTargetPrediction、DrugBank、STITCH及BindingDB数据库检索异鼠李素药理学靶点,应用DisGeNET、GenCLiP及CTD数据库检索缺血性神经损伤的疾病靶点,取交集作为异鼠李素对缺血性神经损伤的治疗靶点,并进行表型分析。将交集靶点导入STRING构建蛋白互作网络,使用Network analyser进行拓扑分析,同时应用MODE构建功能模块,并基于ClueGo对功能模块进行分析。之后应用DAVID数据库对治疗靶点进行GO及KEGG富集分析。利用Discovery Studio评价异鼠李素与核心靶点的结合活性,最后建立OGD/R损伤PC12细胞模型,采用MTT和LDH法检测细胞活力,Western blot法对AKT1、IL6和MMP2的表达进行检测。异鼠李素通过50个缺血性神经损伤相关靶点,调控细胞凋亡、转录、蛋白质磷酸化、炎症反应等生物学过程,干预PI3K-AKT信号通路、HIF-1信号通路、雌激素信号通路、肿瘤坏死因子信号通路、FoxO信号通路等多条途径发挥抗缺血性神经损伤的作用。初步阐释异鼠李素治疗缺血性神经损伤的作用,涉及多靶点、多通路,为进一步探究其药理学活性奠定理论基础。     

Revealing mechanism of Caulis Sargentodoxae for the treatment of ulcerative colitis based on network pharmacology approach

Objective: The traditional Chinese medicine Caulis Sargentodoxae is widely used in the treatment of ulcerative colitis (UC), but the mechanism remains unknown. The present study aims to reveal its effective components, targets and pathways through network pharmacology and bioinformatics approaches.Materials and methods: Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) was used to identify effective components. The ligand-based targets prediction was achieved through SwissTargetPrediction and TargetNet. UC-related targets were identified using Gene Expression Omnibus (GEO) data and DisGeNET. The common targets of disease and components were constructed and analyzed by PPI network. Lastly, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses are used to explain the functions of these common targets. Components-Targets-Pathways network was visualized and analyzed to further reveal the connection between the components and targets.Results: Eight active components and 102 key targets were identified to play an important role in UC. These targets were related to regulation of protein serine/threonine kinase activity, positive regulation of cell motility, response to molecule of bacterial origin, response to toxic substance, ERK1 and ERK2 cascade, peptidyl-tyrosine modification, inositol lipid-mediated signaling, cellular response to drug, regulation of inflammatory response and leukocyte migration. Moreover, HIF-1 signaling pathway and PI3K-Akt signaling pathway were the key targets involved in UC-related signaling pathways.Conclusion: The eight active components of Caulis Sargentodoxae mainly play a therapeutic role for UC through synergistic regulation of HIF-1 signaling pathway and PI3K-Akt signaling pathway.     

Synthesis and identification of novel pyridazinylpyrazolone based diazo compounds as inhibitors of human islet amyloid polypeptide aggregation

We have carried out a docking inspired synthesis and screening of a library of diazenyl-derivatives of pyridazinylpyrazolone molecules for their ability to modulate the amyloidogenic self-assembly of human islet amyloid polypeptide (hIAPP). hIAPP is a 37-residue peptide which is involved in glycemic control along with insulin. Its extracellular fibrillar assemblies in pancreatic β-cells are responsible for type 2 diabetes. A three-step synthetic scheme was used to prepare these novel compounds using 2-(6-chloropyridazin-3-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one as a key intermediate that was reacted with various diazo electrophiles to generate a library of compounds with yields ranging from 64 to 85%. The effect of the compounds on hIAPP amyloid fibril formation was evaluated with a thioflavin T (ThT) fluorescence-based kinetic assay. Furthermore, TEM imaging was carried out to corroborate the interactions of the compounds with hIAPP and subsequent hIAPP inhibition at the different level of fibrillization. The CD spectroscopy showed that upon incubation with SSE15314 for 12 h, the percentage of α-helices was maintained to a level of hIAPP at 0 h. The current study presents identification and characterization of SSE15314 as the hit, which completely inhibited the fibril formation and can be further optimized into a lead compound.     

Molecular docking analysis of the BRCA1 protein with compounds from Justica adhatoda L

BRCA1 is a human tumour suppression gene. Therefore, it is of interest to document the Molecular docking analysis data of the BRCA1 protein with compounds from Justica adhatoda L (adhatoda). We report that Amrinone, Hexadecanoic acid, Pyrazinamide & Vasicinone have acceptable binding features with the BRCA1 protein for further consideration.     

Molecular identification and biological control of Ralstonia solanacearum from wilt of papaya by natural compounds and Bacillus subtilis: An integrated experimental and computational study

Ralstonia solanacearum is a harmful pathogen that causes severe wilt disease in several vegetables. In the present study, we identified R. solanacearum from wilt of papaya by 16S rRNA PCR amplification. Virulence ability of R. solanacearum was determined by amplification of approximately 1500 bp clear band of hrpB gene. Further, in-vitro seed germination assay showed that R. solanacearum reduced the germination rate up to 26.21%, 34% and 33.63% of cucumber, bottle guard and pumpkin seeds, respectively whereas shoot and root growth were also significantly decreased. Moreover, growth inhibition of R. solanacearum was recorded using antibacterial compound from medicinal plant and antagonistic B. subtilis. Petroleum ether root extract of Rauvolfia serpentina showed highest 22 ± 0.04 mm diameter of zone of inhibition where methanolic extract of Cymbopogon citratus and ethanolic extract of Lantana camara exhibited 20 ± 0.06 mm and 20 ± 0.01 mm zone of inhibition against R. solanacearum, respectively. In addition, bioactive compounds of B. subtilis inhibited R. solanacearum growth by generating 17 ± 0.09 mm zone of inhibition. To unveil the inhibition mechanism, we adopted chemical-protein interaction network and molecular docking approaches where we found that, rutin from C. citratus interacts with citrate (Si)-synthase and dihydrolipoyl dehydrogenase of R. solanacearum with binding affinity of −9.7 kcal/mol and −9.5 kcal/mol while quercetin from B. subtillis interacts with the essential protein F0F1 ATP synthase subunit alpha of the R. solancearum with binding affinity of −6.9 kcal/mol and inhibit the growth of R. solanacearum. Our study will give shed light on the development of eco-friendly biological control of wilt disease of papaya.     

Molecular docking analysis of mTOR protein kinase with chromatographically characterized compounds from Clerodendrum inerme L. leaves extract

The mTOR protein is known to be linked with cancer. Therefore, it is of interest to document the molecular docking analysis of mTOR protein kinase with chromatographically characterized compounds from Clerodendrum inerme L. leaves extract. The GC-MS analysis suggested that, totally 25 bioactive compounds were present in the extract of Clerodendrum inerme. Molecular docking analysis show that the bioactive compounds such as Triethoxysilanol, Piperazine dihydrochloridehydrate, 2,4(1H,3H)-Pyrimidinedione, 5-methyl and 4'',7-Dihydroxyflavanone showed good glide score and glide energy within the acceptable and permissible limits of ADME properties for further consideration in drug discovery.     

Molecular mechanisms of An-Chuan Granule for the treatment of asthma based on a network pharmacology approach and experimental validation

An-Chuan Granule (ACG), a traditional Chinese medicine (TCM) formula, is an effective treatment for asthma but its pharmacological mechanism remains poorly understood. In the present study, network pharmacology was applied to explore the potential mechanism of ACG in the treatment of asthma. The tumor necrosis factor (TNF), Toll-like receptor (TLR), and Th17 cell differentiation-related, nucleotide-binding oligomerization domain (NOD)-like receptor, and NF-kappaB pathways were identified as the most significant signaling pathways involved in the therapeutic effect of ACG on asthma. A mouse asthma model was established using ovalbumin (OVA) to verify the effect of ACG and the underlying mechanism. The results showed that ACG treatment not only attenuated the clinical symptoms, but also reduced inflammatory cell infiltration, mucus secretion and MUC5AC production in lung tissue of asthmatic mice. In addition, ACG treatment notably decreased the inflammatory cell numbers in bronchoalveolar lavage fluid (BALF) and the levels of pro-inflammatory cytokines (including IL-6, IL-17, IL-23, TNF-alpha, IL-1beta and TGF-beta) in lung tissue of asthmatic mice. In addition, ACG treatment remarkably down-regulated the expression of TLR4, p-P65, NLRP3, Caspase-1 and adenosquamous carcinoma (ASC) in lung tissue. Further, ACG treatment decreased the expression of receptor-related orphan receptor (RORγt) in lung tissue but increased that of Forkhead box (Foxp3). In conclusion, the above results demonstrate that ACG alleviates the severity of asthma in a ´multi-compound and multi-target’ manner, which provides a basis for better understanding of the application of ACG in the treatment of asthma.     

基于网络药理学和分子对接探讨藏麻黄挥发性成分对支气管炎的作用机制

麻黄(Ephedrae Herba)具有发汗散寒、宣肺平喘、利水消肿的功效。现代研究表明麻黄对治疗支气管、哮喘有疗效。藏麻黄(Ephedra saxatilis)为西藏特有的麻黄属植物,其根、茎具有特殊香气,且目前其挥发性成分未有报道。为评价挥发性成分对支气管炎作用,用气质联用仪测定分析藏麻黄根、茎挥发性成分,并结合网络药理学和分子对接方法分析挥发性成分治疗支气管炎的关键靶点。分析检测到67个挥发性化合物,茎中含有挥发性主要成分为2,3,5,6-四甲基吡嗪(10.92%)、Z-9-十五烯醇(9.15%)、二羟基苯乙酮(7.92%);根含有的挥发性主要成分为亚油酸(7.81%)、红没药醇(7.1%)、Z-9-十五烯醇(5.98%)。有34个挥发性成分能够作用32个支气管炎疾病靶点。蛋白互作网络分析预测IL6、TNF、PTGS2、CXCL8为藏麻黄挥发性成分治疗支气管可能的潜在靶点。这些靶点与挥发性成分丁子香酚、月桂酸、反式法尼醇、α-萜品醇、榄香醇和棕榈酸6种化合物靶点相互结合程度高,且分子对接效果好。本研究推测藏麻黄挥发性成分对支气管炎的治疗作用机制可能是通过抑菌作用参与炎症反应,并通过抑制TNF、IL-17、Toll样受体等炎症与免疫信号通路中IL6、TNF、PTGS2、CXCL8的表达,从而起到治疗支气管炎的作用。研究结果为挖掘藏麻黄挥发性成分中治疗支气管炎靶标分子及其产品开发提供重要参考依据。     

Molecular docking analysis of compounds from Justica adhatoda L with the MUC1 oncoprotein

The MUC1 oncoprotein is known to be linked with different types of cancer. Therefore, it is of interest to document the molecular docking analysis of compounds from Justica adhatoda L with the MUC1 oncoprotein. We report the structure based molecular binding features compounds such as amrinone, ethambutol, pyrazinamide and vasicoline the MUC1 oncoprotein for further consideration in drug discovery.     

Molecular docking analysis of glycogen phosphorylase with inhibitors from Cissampelos pareira Linn.

Cissampelos pareira Linn. is a climbing herb known in Indian traditional medicine as laghupatha. It belongs to the Menispermaceae family. The enzyme glycogen phosphorylase (GP) is a promising target for the treatment of type-2 diabetes (T2DM). A variety of natural product inhibitors with both pharmaceutical and nutraceutical potential have been reported in the search for powerful, selective and drug-like GP inhibitors that could lead to hypoglycemic medicines. Therefore, it is of interest to document the molecular docking analysis data of glycogen phosphorylase with compounds from Cissampelos pareira Linn. We report the optimal binding features of 4 compounds namely Trans-N-feruloyltyramine, Coclaurine, Magnoflorine, and Curine with the target protein for further consideration in the context of T2DM.     

Molecular docking analysis of compounds from Justica adhatoda L with glycogen synthase kinase-3 β

Type 2 diabetes mellitus (T2DM) is linked with Glycogen synthase kinase-3 β.Therefore, it is ofinterest to document molecular docking analysis data of compounds from Justica adhatoda L with glycogen synthase kinase-3 β. We report the binding features of ethambutol, pyrazinamide, stigmasterol and vasicoline with GSK-3 β.     

基于网络药理学、分子对接和实验验证探讨朱茯苓用于失眠的作用机制

为探讨朱茯苓治疗失眠的可能作用机制,通过TCMSP、BAT-MAN、TCMID和STITCH数据库以及文献挖掘筛选朱茯苓的活性成分及潜在靶点,利用TTD、OMIM、GeneCards和CTD数据库获取失眠类疾病的相关靶点,采用Cyto-scape软件和String数据库构建活性成分-靶点网络和靶点蛋白相互作用网络,通过...