ABSTRACT:
Cancer progression involves dysregulation of multiple molecular pathways controlling cell proliferation, apoptosis, and migration. Coffee contains diverse bioactive compounds with reported anticancer properties. However, their multi-target molecular interactions remain insufficiently characterized. This study provides novel insights by systematically evaluating, key proteins in proliferative, apoptotic, and migration pathways targeted by major coffee-derived bioactive compounds. Molecular docking analyses was performed on five major coffee-derived compounds, namely caffeic acid, trigonelline, trimethylpurine-2,6-dione, stigmasterol, and linalool interacting with key proteins involved in proliferation (PI3K, Akt-1, K-Ras, B-Raf), apoptosis (Caspase-8, Caspase-2, Caspase-3), and migration (WNT, MMP-2, MMP-9). Ligand toxicity and physicochemical properties were predicted using ProTox-III and SwissADME, while docking simulations were conducted using CB-Dock 2.0 with AutoDock Vina. Binding affinities and interactions were visualized in 2D and 3D using BIOVIA Discovery Studio. All compounds exhibited low predicted toxicity and acceptable physicochemical parameters. Stigmasterol consistently showed the strongest binding affinities across all protein targets, comparable to reference inhibitors, predominantly stabilized by hydrophobic interactions. Caffeic acid demonstrated moderate but stable binding through multiple hydrogen bonds with catalytic residues, particularly within PI3K, B-Raf, and Caspase families. These findings suggest that stigmasterol and caffeic acid act as complementary multi-target ligands capable of modulating key oncogenic pathways related to proliferation, apoptosis, and migration. Their interaction profiles highlight coffee bioactives as potential candidates for further investigation in multi-target cancer therapy. However, these findings are based on computational predictions and require further validation through experimental studies.