Drug Repurposing of Metformin as a γ-Secretase Modulator in Cancer therapy

Abstract

A computational approach(in-silico) combined with molecular docking, binding analysis, and interaction profiling was done to evaluate metformin’s affinity for the γ-secretase complex. Known γ-secretase binders—including Avagacestat, Semagacestat, Nirogacestat, RO4929097, and CD147—were used as positive controls for the comparative study and analysis of docking parameters. Metformin demonstrated a favourable binding affinity despite its small size and hydrophilic nature, forming 2 stable hydrogen bonds with critical residues in the receptor’s binding pocket. Comparison with established binders showed overlapping interaction sites, suggesting that metformin could influence γ-secretase activity directly or indirectly. Assessment of hydrogen bonding and atomic contact scores further confirmed the stability and specificity of these interactions. This study highlights metformin as a promising candidate for repurposing as an anticancer agent, potentially targeting both γ-secretase–Notch signaling and cancer metabolism. While the computational results provide strong preliminary evidence, further experimental validation in cell and animal models(in-vitro) is necessary to confirm the biological significance of these interactions. This work demonstrates the value of integrating computational and mechanistic approaches to identify new applications for existing drugs in cancer therapy.