Traditionally, Withania somnifera is widely used as an immune booster, anti-viral, and for multiple medicinal purposes. The present study investigated the withanolides as an immune booster and anti-viral agents against the coronavirus-19. Withanolides from Withania somnifera were retrieved from the open-source database, their targets were predicted using DIGEP-Pred, and the protein-protein interaction was evaluated. The drug-likeness score and intestinal absorptivity of each compound were also predicted. The network of compounds, proteins, and modulated pathways was constructed using Cytoscape, and docking was performed using autodock4.0, and selected protein-ligand complexes were subjected to 100 ns Molecular Dynamics simulations. The molecular dynamics trajectories were subjected to free energy calculation by the MM-GBSA method. Withanolide_Q was predicted to modulate the highest number of proteins, showed human intestinal absorption, and was predicted for the highest drug-likeness score. Similarly, combined network interaction identified Withanolide_Q to target the highest number of proteins; RAC1 was majorly targeted, and fluid shear stress and atherosclerosis associated pathway were chiefly regulated. Similarly, Withanolide_D and Withanolide_G were predicted to have a better binding affinity with PLpro, Withanolide_M with 3CLpro, and Withanolide_M with spike protein based on binding energy and number of hydrogen bond interactions. MD studies suggested Withanoside_I with the highest binding free energy (ΔG_bind-31.56 kcal/mol) as the most promising inhibitor. Among multiple withanolides from W. somnifera, Withanolide_D, Withanolide_G, Withanolide_M, and Withanolide_Q were predicted as the lead hits based on drug-likeness score, modulated proteins, and docking score to boost the immune system and inhibit the COVID-19 infection, which could primarily act against COVID-19. Communicated by Vsevolod Makeev Graphical Abstract

Anthraquinone derivatives are identified for their immune-boosting, anti-inflammatory, and anti-viral efficacy. Hence, the present study aimed to investigate the reported anthraquinone derivatives as immune booster molecules in COVID-19 infection and evaluate their binding affinity with three reported targets of novel coronavirus i.e. 3C-like protease, papain-like protease, and spike protein. The reported anthraquinone derivatives were retrieved from an open-source database and filtered based on a positive druglikeness score. Compounds with positive druglikeness scores were predicted for their targets using DIGEP-Pred and the interaction among modulated proteins was evaluated using STRING. Further, the associated pathways were recorded concerning the Kyoto Encyclopedia of Genes and Genomes pathway database. Finally, the docking was performed using autodock4 to identify the binding efficacy of anthraquinone derivatives with 3C-like protease, papain-like protease, and spike protein. After docking the pose of ligand scoring minimum binding energy was chosen to visualize the ligand–protein interaction. Among 101 bioactives, 36 scored positive druglikeness score and regulated multiple pathways concerned with immune modulation and (non-) infectious diseases. Similarly, docking study revealed torososide B to possess the highest binding affinity with papain-like protease and 3C-like protease and 1,3,6-trihydroxy-2-methyl-9,10-anthraquinone-3-O-(6′-O-acetyl)-β-d-xylopyranosyl-(1 → 2)-β-d-glucopyranoside with spike protein. Graphic

Background: Tinospora cordifolia is used traditionally for the treatment of diabetes and is used in various formulations. Scientific evidence is also available for its anti-diabetic potency under various animal models. However, the probable molecular mechanism of Tinospora cordifolia in the treatment of diabetes has not been illuminated yet. Hence, the present study dealt to elucidate the probable molecular mechanism of anti-diabetic effect of Tinospora cordifolia using network pharmacology approach. Methods: The structural information of bioactive phytoconstituents was retrieved from different open source databases. Compounds were then predicted for their hits with the probable targets involved in the diabetes mellitus. Phytoconstituents were also predicted for their druglikeness score, probable side effects, and ADMET profile. The modulated protein pathways were identified by using the Kyoto Encyclopedia of Genes and Genomes pathway analysis. The interaction between the compounds, proteins, and pathways was interpreted based on the edge count. The docking study was performed using Autodock4.0. Results: Nine phytoconstituents from Tinospora cordifolia were identified to modulate the pathogenic protein molecules involved in diabetes mellitus. Among them, tembetarine scored highest druglikeness hit and had the maximum interaction with proteins involved in diabetes. Further, neuroactive ligand-receptor interaction was predicted as majorly modulated pathway. Conclusion: The current study identified an important antidiabetic constituent, tembetarine which modulated the majority of diabetic proteins majorly modulating neuroactive ligand-receptor interaction.

Aim: The purpose of this study was to establish a mode of action for diosgenin against breast cancer employing a range of system biology tools and to corroborate its results with experimental facts.Methodology: The diosgenin-regulated domains implicated in breast cancer were enriched in the Kyoto Encyclopedia of Genes and Genomes database to establish diosgenin-protein(s)-pathway(s) associations. Later, molecular docking and the lead complexes were considered for molecular dynamics simulations, MMPBSA, principal component, and dynamics cross-correlation matrix analysis using GROMACS v2021. Furthermore, survival analysis was carried out for the diosgenin-regulated proteins that were anticipated to be involved in breast cancer. For gene expression analyses, the top three targets with the highest binding affinity for diosgenin and tumor expression were examined. Furthermore, the effect of diosgenin on cell proliferation, cytotoxicity, and the partial Warburg effect was tested to validate the computational findings using functional outputs of the lead targets.Results: The protein-protein interaction had 57 edges, an average node degree of 5.43, and a p-value of 3.83e-14. Furthermore, enrichment analysis showed 36 KEGG pathways, 12 cellular components, 27 molecular functions, and 307 biological processes. In network analysis, three hub proteins were notably modulated: IGF1R, MDM2, and SRC, diosgenin with the highest binding affinity with IGF1R (binding energy −8.6 kcal/mol). Furthermore, during the 150 ns molecular dynamics (MD) projection run, diosgenin exhibited robust intermolecular interactions and had the least free binding energy with IGF1R (−35.143 kcal/mol) compared to MDM2 (−34.619 kcal/mol), and SRC (-17.944 kcal/mol). Diosgenin exhibited the highest cytotoxicity against MCF7 cell lines (IC₅₀ 12.05 ± 1.33) µg/ml. Furthermore, in H₂O₂-induced oxidative stress, the inhibitory constant (IC₅₀ 7.68 ± 0.51) µg/ml of diosgenin was lowest in MCF7 cell lines. However, the reversal of the Warburg effect by diosgenin seemed to be maximum in non-cancer Vero cell lines (EC₅₀ 15.27 ± 0.95) µg/ml compared to the rest. Furthermore, diosgenin inhibited cell proliferation in SKBR3 cell lines more though.Conclusion: The current study demonstrated that diosgenin impacts a series of signaling pathways, involved in the advancement of breast cancer, including FoxO, PI3K-Akt, p53, Ras, and MAPK signaling. Additionally, diosgenin established a persistent diosgenin-protein complex and had a significant binding affinity towards IGF1R, MDM2, and SRC. It is possible that this slowed down cell growth, countered the Warburg phenomenon, and showed the cytotoxicity towards breast cancer cells.

Cassia glauca is reported for anti-diabetic action and is also used as an ethnomedicine.

The present study aimed to investigate the binding affinity of andrographolide and its derivative i.e., 14-deoxy-11,12-didehydroandrographolide with targets related to COVID-19 and their probable role in regulating multiple pathways in COVID-19 infection. SMILES of both compounds were retrieved from the PubChem database and predicted for probably regulated proteins. The predicted proteins were queried in STRING to evaluate the protein–protein interaction, and modulated pathways were identified concerning the KEGG database. Drug-likeness and ADMET profile of each compound was evaluated using MolSoft and admetSAR 2.0, respectively. Molecular docking was carried using Autodock 4.0. Andrographolide and its derivative were predicted to have a high binding affinity with papain-like protease, coronavirus main proteinase, and spike protein. Molecular dynamics simulation studies were performed for each complex which suggested the strong binding affinities of both compounds with targets. Network pharmacology analysis revealed that both compounds modulated the immune system by regulating chemokine signaling, Rap1 signaling, cytokine–cytokine receptor interaction, MAPK signaling, NF-kappa B signaling, RAS signaling, p53 signaling, HIF-1 signaling, and natural killer cell-mediated cytotoxicity. The study suggests strong interaction of andrographolide and 14-deoxy-11,12-didehydroandrographolide against COVID-19 associated target proteins and exhibited different immunoregulatory pathways.