Homology Modeling, Screening, and Identification of Potential FOXO6 Inhibitors Curtail Gastric Cancer Progression: an In Silico Drug Repurposing Approach

Gastric cancer is the world's second leading cause of cancer-related fatalities, with the epidemiology changing over the previous several decades. FOXOs are the O subfamily of the forkhead box (FOX) transcription factor family, which consists of four members: FOXO1, FOXO3, FOXO4, and FOXO6. FOXO6 mRNA and protein levels are increased in gastric cancer tissues. FOXO6 forced overexpression enhances gastric cancer cell growth, while knockdown decreases proliferation. In our study, the GEPIA, Kaplan-Meier, KEGG, and STRING databases were used to determine FOXO6 mRNA expression, overall survival ratio, interactive pathways, and top 10 associated proteins in gastric cancer respectively. Due to the lack of a solved structure for FOXO6, homology modeling was performed to obtain a 3D structure model, and we used anti-cancer drugs and small molecules to target FOXO6 for identifying a potential selective FOXO6 inhibitor. The chemical composition of the proteins and ligands has a significant impact on docking procedure performance. With this in mind, a critical evaluation of the performance of three regularly used docking routines was carried out: MVD, AutoDock Vina in PyRx, and ArgusLab. The binding affinities, docking scores, and intermolecular interactions were used as assessment criteria. In the study, the porfimer sodium showed excellent binding affinity to the FOXO6 protein. The major three docking software packages were used to analyze the scoring/H-bonding energy and intermolecular interactions. Based on the results, we concluded that FOXO6 was upregulated in gastric cancer and the ligand porfimer sodium emerges as a promising potential FOXO6 inhibitor to curtail gastric cancer progression.