Investigation of simvastatin and fluvastatin permeation across cell membrane models using molecular dynamics simulations

Abstract

The chief motivation for the failure of drugs in clinical trials is their low bioavailability caused by the inability to cross the cell membrane. Understanding drug–membrane interactions is crucial for improving therapeutic efficacy. In this work, molecular dynamics simulations were employed to investigate the permeation of simvastatin and fluvastatin across three lipid bilayer models representing normal and cancer cell membranes. Free energy profiles reveal that simvastatin, due to its higher lipophilicity, interacts more strongly with lipid environments, preferentially permeating cancer-like symmetric membranes. Fluvastatin, in contrast, shows less selective behavior across different membrane types, consistent with its charged nature. Statin insertion perturbs membrane structure, increasing area per lipid and decreasing bilayer thickness and lipid order. These findings highlight how membrane composition and asymmetry govern passive drug diffusion and suggest that selective membrane interactions may reflect the differential anticancer potential of statins. The results provide mechanistic insights into structure–permeability relationships and support the strategic use of realistic membrane models in drug discovery and repurposing efforts.