MOLECULAR DOCKING-BASED EVALUATION OF QUERCETIN AS A MULTI-TARGET THERAPEUTIC AGENT IN ESTROGEN-ASSOCIATED GALLBLADDER CARCINOGENESIS

Abstract

Gallbladder carcinoma (GBC) is an intense and highly invasive malignant cancer of the biliary tract associated with unfavourable prognosis and high mortality due to late-stage diagnosis. Chronic inflammation, oxidative stress, hormonal imbalance, and dysregulation of signaling pathways such as PI3K/AKT, MAPK, and NF-κB play major roles in the progression of estrogen-associated gallbladder carcinogenesis. Estrogen-mediated signaling further contributes to tumour development by promoting gallstone formation, abnormal cell proliferation, angiogenesis, and resistance to apoptosis. Considering the complex and multi-factorial nature of gallbladder cancer, there is a growing need for therapeutic agents capable of targeting multiple molecular pathways simultaneously. The present study aimed to evaluate the multi-target therapeutic potential of quercetin, a naturally occurring flavonoid, against estrogen-associated gallbladder carcinogenesis using molecular docking and network pharmacology approaches. Potential protein targets of quercetin were identified using SwissTargetPrediction, while gallbladder disease- associated genes were collected from GeneCards. Key hub proteins including AKT1, PIK3CA, EGFR, SRC, and BRAF were selected for further investigation. Molecular docking studies were performed using PyRx integrated with AutoDock Vina. Among the selected proteins, AKT1 exhibited the strongest binding affinity with quercetin, showing a docking score of approximately −9.7 kcal/mol, indicating stable and favourable interaction. Interaction analysis demonstrated the presence of multiple hydrogen bonds and hydrophobic interactions within the active binding site, confirming structural compatibility between quercetin and the target protein. Visualization studies using PyMOL and Discovery Studio further validated the docking results. The findings of this study suggest that quercetin possesses significant multi-target therapeutic potential by modulating critical signalling pathways involved in gallbladder carcinogenesis, particularly the PI3K/AKT pathway. Therefore, quercetin may serve as a promising natural compound for the development of future therapeutic strategies against estrogen-associated gallbladder cancer. Further in vitro, in vivo, and clinical studies are recommended to validate its therapeutic efficacy and safety.