Many approved pharmaceuticals for cancer, heart failure, inflammatory diseases, and others act from within the cells. These drugs belong to different classes that range from relatively large hydrophobic molecules to small charge carrying ones, giving rise to uncertainties as to how they interact with the cell membrane. Very little is known in regards to the basic mechanism by which these intracellular drugs enter the cells. Experimental studies have shown that the accumulation of drugs such as vincristine and doxorubicin in cells and lipid vesicles is proportional to the concentration of cholesterol1,2. In particular, it is not known whether drugs bind and partition into the specific regions of the cell membrane, or whether drug-lipid interactions are mediated by the concentration of different lipid species in the cell membrane.
In this study, we use molecular dynamics (MD) simulation techniques to determine whether the partitioning of different drug classes into the membrane preferentially occurs in lipid domains with high cholesterol. Using unbiased MD simulations, we examined the binding and partitioning of the opioid drug morphine, the calcium channel blockers nicardipine and verapamil, and the cancer chemotherapeutics doxorubicin, vincristine and paclitaxel into pure POPC membranes or POPC membranes enriched with cholesterol. The free energy profile for each compound as it partitions into a membrane from the aqueous environment was determined using umbrella sampling techniques. The effect of the drugs on the physical properties of the membrane was also examined.