Terminalia chebula Retz. forms a key component of traditional folk medicine and is also reported to possess antihepatitis C virus (HCV) and immunomodulatory activities. However, information on the intermolecular interactions of phytochemicals from this plant with HCV and human proteins are yet to be established. Thus, by this current study, we investigated the HCV NS3/4A inhibitory and host immune-modulatory activity of phytocompounds from T. chebula through in silico strategies involving network pharmacology and structural bioinformatics techniques. To start with, the phytochemical dataset of T. chebula was curated from biological databases and the published literature. Further, the target ability of the phytocompounds was predicted using BindingDB for both HCV NS3/4A and other probable host targets involved in the immune system. Further, the identified targets were docked to the phytochemical dataset using AutoDock Vina executed through the POAP pipeline. The resultant docked complexes with significant binding energy were subjected to 50 ns molecular dynamics (MD) simulation in order to infer the stability of complex formation. During network pharmacology analysis, the gene set pathway enrichment of host targets was performed using the STRING and Reactome pathway databases. Further, the biological network among compounds, proteins, and pathways was constructed using Cytoscape 3.6.1. Furthermore, the druglikeness, side effects, and toxicity of the phytocompounds were also predicted using the MolSoft, ADVERpred, and PreADMET methods, respectively. Out of 41 selected compounds, 10 were predicted to target HCV NS3/4A and also to possess druglike and nontoxic properties. Among these 10 molecules, Chebulagic acid and 1,2,3,4,6-Pentagalloyl glucose exhibited potent HCV NS3/4A inhibitory activity, as these scored a lowest binding energy (BE) of −8.6 kcal/mol and −7.7 kcal/mol with 11 and 20 intermolecular interactions with active site residues, respectively. These findings are highly comparable with Asunaprevir (known inhibitor of HCV NS3/4A), which scored a BE of −7.4 kcal/mol with 20 key intermolecular interactions. MD studies also strongly suggest that chebulagic acid and 1,2,3,4,6-Pentagalloyl glucose as promising leads, as these molecules showed stable binding during 50 ns of production run. Further, the gene set enrichment and network analysis of 18 protein targets prioritized 10 compounds and were predicted to potentially modulate the host immune system, hemostasis, cytokine levels, interleukins signaling pathways, and platelet aggregation. On overall analysis, this present study predicts that tannins from T. chebula have a potential HCV NS3/4A inhibitory and host immune-modulatory activity. However, further experimental studies are required to confirm the efficacies.

Background and objective: Doxorubicin is a widely used chemotherapeutic agent that causes oxidative stress leading to cardiotoxicity, hepatotoxicity, and nephrotoxicity. In contrast, Theobroma cacao L. has been recorded as an anticancer agent and found to be protective against multiple chemical-induced organ injuries, including heart, liver, and kidney injuries. The present study investigated the possible role of extracts from T. cacao beans for organ-protective effects in doxorubicin-induced toxicity in mice bearing Ehrlich ascites carcinoma (EAC). Methodology: After survival analysis in rodents, cocoa bean extract (COE) was investigated for its efficacy against EAC-induced carcinoma and its organ-protective effect against doxorubicin-treated mice with EAC-induced carcinoma. Results: Significant reductions in EAC and doxorubicin-induced alterations were observed in mice administered the COE, either alone or in combination with doxorubicin. Furthermore, COE treatment significantly increased the mouse survival time, life span percentage, and antioxidant defense system. It also significantly improved cardiac, hepatic, and renal function biomarkers and markers for oxidative stress, and it also reduced doxorubicin-induced histopathological changes. Conclusion: COE acted against doxorubicin-induced organ toxicity; potent antioxidant and anticancer activities were also reflected by the COE itself. The COE may therefore serve as an adjuvant nutraceutical in cancer chemotherapy.

Herbs are widely utilized in the Western Ghats region of India to treat liver diseases and viral-like infections. However, such practices lack scientific evidence at the molecular level and may often pose adverse drug reactions. This study intends to identify phytocompounds with druggability and non-toxic profiles with potential activity against hepatitis B virus-induced hepatocellular carcinoma. The details of phytocompounds in traditionally utilized herbs in the Western Ghats region were collated from chemical databases and publications. The druggability and toxicity of these compounds were predicted using MolSoft and ADVERpred, respectively. The probable targets of these phytocompounds were predicted using BindingDB. Moreover, compound-gene set pathways, cellular processes, and functional enrichment analyses were also performed using STRING and KEGG pathway databases. Subsequently, herb–compound–target–disease pathway networks were constructed using Cytoscape. The potential hub protein was virtually screened against the ligand dataset using the POAP pipeline. Finally, molecular dynamics (MD) simulations of the most potential protein–ligand complexes were performed in triplicate using Schrödinger Desmond. Amongst 274 compounds from 16 herbs studied, 36 showed drug-likeness with nontoxic properties and were also predicted to modulate 16 potential targets involved in the pathogenesis of HBV-induced HCC. Among all the molecules screened, flavonoids and diterpenoids from Andrographis paniculata and Thespesia populnea scored the highest edge count via modulating multiple targets and pathways. Moreover, molecular docking and MD simulation (100ns) also inferred that the top-ranking Andrographin and Gossypetin exhibit stable intermolecular interactions with EGFR protein, which was identified as a highly connected hub protein in the constructed network. All these findings are suggestive of identified moieties as potential therapeutics for targeting HBV-associated HCC sans adverse drug reactions.

Background: Barringtonia acutangula (L.) Gaertn, Garcinia indica (Thouars) Choisy, and Feronia limonia (L.) Swingle is widely utilized in traditional folk medicine against diabetes, obesity, and metabolic syndrome but lacks the evidence of compound-protein interaction for the treatment. Methods: Phytocompounds were retrieved from herbs databases and public repositories. Probable protein targets were predicted using BindingDB (p ≥ 0.7). The pathways modulated by compounds were analyzed using the STRING and KEGG pathways. The compound-protein-pathway network was constructed using Cytoscape v3.6.1. Druglikeness was predicted by Molsoft. Docking was performed by AutoDock vina by PyRx 0.8v. Results: Among three plants, eleven triterpene saponins from B. acutangula showed druggable characteristics and identified to inhibit the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1/HSD11B1) as a key protein target and also inhibit/modulate other 27 protein molecules involved in the 3 major pathways i.e. Metabolic syndrome, cGMP-PKG signaling, and insulin resistance pathways and also these compounds showed interactions with the active site amino acid residues of 11β-HSD1. Among eleven compounds Barringtogenol B scored the highest binding affinity by forming a hydrogen bond with Ile218 active site residue of 11β-HSD1. Conclusion: Triterpene saponins contained in B. acutangula bark and seed inhibits 11Β-HSD1 and this multi-compound contained enriched fraction could be the potent treatment regimen for T2DM, obesity, and MetS.

Hepatitis B infection caused by the hepatitis B virus is a life-threatening cause of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Researchers have produced multiple in vivo models for hepatitis B virus (HBV) and, currently, there are no specific laboratory animal models available to study HBV pathogenesis or immune response; nonetheless, their limitations prevent them from being used to study HBV pathogenesis, immune response, or therapeutic methods because HBV can only infect humans and chimpanzees. The current study is the first of its kind to identify a suitable chemically induced liver cirrhosis/HCC model that parallels HBV pathophysiology. Initially, data from the peer-reviewed literature and the GeneCards database were compiled to identify the genes that HBV and seven drugs (acetaminophen, isoniazid, alcohol, D-galactosamine, lipopolysaccharide, thioacetamide, and rifampicin) regulate. Functional enrichment analysis was performed in the STRING server. The network HBV/Chemical, genes, and pathways were constructed by Cytoscape 3.6.1. About 1546 genes were modulated by HBV, of which 25.2% and 17.6% of the genes were common for alcohol and lipopolysaccharide-induced hepatitis. In accordance with the enrichment analysis, HBV activates the signaling pathways for apoptosis, cell cycle, PI3K-Akt, TNF, JAK-STAT, MAPK, chemokines, NF-kappa B, and TGF-beta. In addition, alcohol and lipopolysaccharide significantly activated these pathways more than other chemicals, with higher gene counts and lower FDR scores. In conclusion, alcohol-induced hepatitis could be a suitable model to study chronic HBV infection and lipopolysaccharide-induced hepatitis for an acute inflammatory response to HBV.