Structural basis of polypharmacological effects of metformin

Metformin is the first-line drug of choice for the treatment of type 2 diabetes. Recently, it was found that clinically achievable concentrations of metformin cause significant death of cancer cells in culture. Existing evidences connect its anti-cancer effects to the inhibition of the mTOR signaling pathway, but the actual molecular targets remain unknown. In this study, proteome-wide ligand binding site analysis, reverse protein-ligand docking, and quantum mechanics are used to search for the potential molecular targets of metformin. Our results suggest that metformin may bind to β-subunit of AMP-Activated Protein Kinase (AMPK), and active AMPK through allosteric regulation. Several off-targets that are directly or indirectly involved in mTOR pathways are identified. These results generate a tractable set of anti-cancer protein targets for experimental validations.