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Curcumin is a hydrophobic polyphenol derived from turmeric with potent anti-oxidant, anti-microbial, anti-inflammatory and anti-carcinogenic effects. Curcumin is degraded into various derivatives under in vitro and in vivo conditions, and it appears that its degradation may be responsible for the pharmacological effects of curcumin. The primary risk factor for the cause of gastric cancer is Helicobacter pylori (H. pylori) . A virulence factor vacuolating cytotoxic A (VacA) is secreted by H. pylori as a 88 kDa monomer (p88), which can be fragmented into a 33 kDa N-terminal domain (p33) and a 55 kDa C-terminal domain (p55). Recently it has been reported that curcumin oxidation is required to inhibit the activity of another major H.pylori toxin CagA. We performed molecular docking of curcumin and its oxidative derivatives with p33 and p55 domains of VacA. Further, we have examined the effect of the oxidation of curcumin on the vacuolation activity of VacA protein. We observed the binding of curcumin to the p55 domain of VacA at five different sites with moderate binding affinities. Curcumin did not bind to p33 domain of VacA. Remarkably, cyclobutyl cyclopentadione and dihydroxy cyclopentadione, which are oxidized products of curcumin, showed a higher binding affinity with VacA protein at all sites except one as compared to parent curcumin itself. However, cyclobutyl cyclopentadione showed a significant binding affinity for the active site 5 of the p55 protein. Active site five (312-422) of p55 domain of VacA plays a crucial role in VacA-mediated vacuole formation. Invitro experiments showed that curcumin inhibited the vacuolation activity of H. pylori in human gastric cell line AGS cells whereas acetyl and diacetyl curcumin, which cannot be oxidized, failed to inhibit the vacuolation in AGS cells after H. pylori infection. Here our data showed that oxidation is essential for the activity of curcumin in inhibiting the vacuolation activity of H. pylori . Synthesis of these oxidized curcumin derivatives could potentially provide new therapeutic drug molecules for inhibiting H. pylori -mediated pathogenesis.

Curcumin is an important bioactive component of turmeric and also one of the important natural products, which has been investigated extensively. The precise mode of action of curcumin and its impact on system level protein networks are still not well studied. To identify the curcumin governed regulatory action on protein interaction network (PIN), an interectome was created based on 788 key proteins, extracted from PubMed literatures, and constructed by using STRING and Cytoscape programs. The PIN rewired by curcumin was a scale-free, extremely linked biological system. MCODE plug-in was used for sub-modulization analysis, wherein we identified 25 modules; ClueGo plug-in was used for the pathway's enrichment analysis, wherein 37 enriched signalling pathways were obtained. Most of them were associated with human diseases groups, particularly carcinogenesis, inflammation, and infectious diseases. Finally, the analysis of topological characteristic like bottleneck, degree, GO term/pathways analysis, bio-kinetics simulation, molecular docking, and dynamics studies were performed for the selection of key regulatory proteins of curcumin-rewired PIN. The current findings deduce a precise molecular mechanism that curcumin might exert in the system. This comprehensive in-silico study will help to understand how curcumin induces its anti-cancerous, anti-inflammatory, and anti-microbial effects in the human body.

Caspase-3 has been identified as a key mediator of neuronal apoptosis. The present study identifies caspase-3 as a common player involved in the regulation of multineurodegenerative disorders, namely, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The protein interaction network prepared using STRING database provides a strong evidence of caspase-3 interactions with the metabolic cascade of the said multineurodegenerative disorders, thus characterizing it as a potential therapeutic target for multiple neurodegenerative disorders. In silico molecular docking of selected nonpeptidyl natural compounds against caspase-3 exposed potent leads against this common therapeutic target. Rosmarinic acid and curcumin proved to be the most promising ligands (leads) mimicking the inhibitory action of peptidyl inhibitors with the highest Gold fitness scores 57.38 and 53.51, respectively. These results were in close agreement with the fitness score predicted using X-score, a consensus based scoring function to calculate the binding affinity. Nonpeptidyl inhibitors of caspase-3 identified in the present study expeditiously mimic the inhibitory action of the previously identified peptidyl inhibitors. Since, nonpeptidyl inhibitors are preferred drug candidates, hence, discovery of natural compounds as nonpeptidyl inhibitors is a significant transition towards feasible drug development for neurodegenerative disorders.

• Curcumin exhibited higher binding affinity with CagA compared to its non-oxidizable derivatives. • Curcumin was found to bind to the active pocket in the CTD of the CagA protein. This pocket is made up of the EPIYA-C motif and the CM motif. • Curcumin interacted with the TYR970 residue, known to undergo phosphorylation during H. pylori -mediated pathogenesis. • The OH-group located on the phenol ring of curcumin appears to play a crucial role in curcumin oxidation and the inhibition of CagA phosphorylation. • Curcumin's anti- H. pylori activity may be linked to inhibiting the phosphorylation of the CagA oncoprotein. Helicobacter pylori is a pathogenic bacterium that causes various gastric diseases in humans. It secretes virulence factors such as the CagA protein, which plays a crucial role in its pathogenesis. The C-terminal domain (CTD) of the CagA protein plays a crucial role in facilitating its attachment to host cell membranes and interacting with various intracellular proteins. These interactions are essential for the growth and infection of H. pylori. Strain-specific sequence polymorphism of H. pylori , specifically at the C-terminal of the CagA protein, is responsible for its differential oncogenic potential. Curcumin is a natural compound with pharmacological properties like anti-oxidant, anti-bacterial, anti-inflammatory, and anti-cancer effects. Additionally, several studies have reported the anti- H. pylori effects of curcumin. In this study, we investigated mechanisms of binding of curcumin and its non-oxidizable derivatives (acetalcurcumin and diacetalcurcumin) with CTD of CagA protein. We used computational strategies such as docking and molecular dynamics simulation for the analysis. Curcumin was found to have more binding affinity with the CagA protein than its acetal and diacetal analogs. This suggests that the OH-group present in the structure of curcumin, which gets modified in its acetal and diacetal analogs, may have an essential role in the interaction with the CagA protein. Results showed that curcumin binds to the residues within the active pocket formed by the EPIYA-C motif and CM motif located in the C-terminal domain (CTD) of the CagA protein. Additionally, curcumin was observed to interact with the TYR970 residue within the EPIYA-C motif of the CTD of the CagA protein. Notably, TYR970 phosphorylation is a known event during H. pylori- mediated pathogenesis. Therefore, this study suggests that curcumin's anti- H. pylori activity may be triggered by inhibiting the phosphorylation of the CagA protein. [Display omitted] [ABSTRACT FROM AUTHOR]