A Network Pharmacological Approach to Reveal the Pharmacological Targets and Its Associated Biological Mechanisms of Prunetin-5-O-Glucoside against Gastric Cancer

Abstract

Simple Summary Identification of pharmacological targets in cancer provides a major walkthrough toward treatment strategies. The present research adopted a network pharmacology approach utilizing a flavonoid glucoside prunetin-5-O-glucoside (PG) compound against gastric cancer. The correlative targets were analyzed using Swiss target prediction and DiGeNET databases. Functional enrichment and significant pathways enriched were predicted for the targets to associate its biological mechanisms with cancer. Protein interaction network and cluster analysis was performed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). Our analysis revealed three core targets among the clustered modules that plays a crucial role in relation with cancer. With this information, the core targets were examined for the binding affinity with PG using molecular docking analysis and validations on the protein targets was performed using western blot analysis and Human Protein Atlas. Our analysis through comprehensive network pharmacology resulted in the prediction of three core targets of PG that can be significant biomarkers against gastric cancer. Gastric cancer (GC) is an aggressive malignancy with increased mortality rate and low treatment options. Increasing evidence suggests that network pharmacology will be a novel method for identifying the systemic mechanism of therapeutic compounds in diseases like cancer. The current study aimed to use a network pharmacology approach to establish the predictive targets of prunetin-5-O-glucoside (PG) against gastric cancer and elucidate its biological mechanisms. Primarily, genes associated with the pathogenesis of GC was identified from the DiGeNET database and targets of PG was obtained from the Swiss target prediction database. In total, 65 correlative hits were identified as anti-gastric cancer targets of PG. Functional enrichment and pathway analysis revealed significant biological mechanisms of the targets. Interaction of protein network and cluster analysis using STRING resulted in three crucial interacting hub targets namely, HSP90AA1, CDK2, and MMP1. Additionally, the in vitro cytotoxic potential of PG was assessed on three gastric cancer cells (AGS, MKN-28, and SNU-484). Furthermore, the crucial targets were validated using molecular docking, followed by their expressions being evaluated by western blot and Human Protein Atlas. The findings indicate that the pharmacological action of PG against GC might be associated with the regulation of three core targets: HSP90AA1, CDK2, and MMP1. Thus, the network pharmacology undertaken in the current study established the core active targets of PG, which may be extensively applied with further validations for treatment in GC.