Computational Identification of GSK3B Inhibitors for Treatment of Gastric Cancer

Introduction: Glycogen synthase kinase-3 beta (GSK3B) is known to play a role in the progression of gastric cancer, particularly through the regulation of major oncogenic pathways such as Wnt/β-catenin and apoptosis. The aim of this study was to computationally screen and assess the potential GSK3B inhibitors for the treatment of gastric cancer. Materials and Methods: Screening with ligands from databases, such as ChEMBL, DrugBank, and IMPPAT, against the homology-modelled GSK3B structure in in silico. Molecular docking was performed using AutoDock Vina and analyzed by AutoDock4. ADMET properties and contact profiles were analyzed computationally. Complexes of top candidates are allowed to do 1 μs molecular dynamics (MD) simulations, principal component analysis (PCA), and density functional theory (DFT) calculations. Results: CHEMBL3347331 and DB12937 have emerged as the most promising inhibitors, showing the best favorable docking scores (-8.237 and -6.932 kcal/mol respectively). ADMET predictions showed good oral bioavailability and lack of off-target toxicities. These ligands showed stable binding throughout the 1 μs MD simulations. Interaction analyses showed persistent hydrogen bonding and hydrophobic interactions. Energetically most favourable DFT descriptors, such as HOMOLUMO gaps (3.356 and 3.345 eV), showed that the chemical stability of ligands. The reference inhibitors Tideglusib and AZD1080 were used for comparative benchmarking. Discussion: The present computational study draws attention to CHEMBL3347331 and DB12937 as potential GSK3B inhibitors, which showed similar stability and binding properties. The limitations of the present study are that it is based only on in silico predictions and lacks in vitro and in vivo validation, and ADMET studies may not be comprehensive enough to represent the biological complexity. Conclusion: CHEMBL3347331 and DB12937 are promising computationally identified candidates for further investigation as GSK3B-targeted inhibitors in the context of gastric cancer. Future studies should include biochemical, cell-based, animal model studies, and analysis of GSK3B expression and mutation status in gastric cancer to validate efficacy and safety.