Simvastatin (Zocor©) is one of the most prescribed drugs for reducing high cholesterol. Although simvastatin is ingested in its inactive lactone form, it is converted to its active dihydroxyheptanoate form by carboxylesterases in the liver. The dihydroxyheptanoate form can also be converted back to its original lactone form. Unfortunately, some of the side effects associated with the intake of simvastatin and other lipophilic statins at higher doses include statin-associated myopathy (SAM) and in more severe cases, kidney failure. While the cause of SAM is unknown, it is hypothesized that these side effects are dependent on the localization of statins in lipid bilayers and their impact on bilayer properties. In this work, we carry out all-atom molecular dynamics simulations on both the lactone and dihydroxyheptanoate forms of simvastatin (termed ‘SN’ and ‘SA’ respectively) with a pure POPC lipid bilayer and a POPC/cholesterol (30 mol%) binary mixture as membrane models. Additional simulations were carried out with multiple simvastatin molecules in order to mimic in vitro conditions that produced pleiotropic effects. Both SN and SA spontaneously diffused into the lipid bilayer, and a longer simulation time of 4 μs was needed for complete incorporation of multiple SAs into the bilayers. By constructing potential mean force and electron density profiles, we find that SN localizes deeper within the hydrophobic interior of the bilayer, and that SA has a greater tendency to form hydrogen bonding interactions with neighboring water molecules and lipid head groups. For the pure POPC bilayer, both SN and SA increases membrane order, while membrane fluidity increases for the POPC/cholesterol bilayer.

Modulation of phospholipid bilayer properties by simvastatin

ACS Fall 2021

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