Drugs-membrane interactions are inevitable, since absorption and even therapeutic action depend on it. The action of a drug may result in the disturbance of the biophysical properties of the membrane. This can result either in therapeutic or in toxic effects. Different experimental techniques are available to measure the influence of drugs on membrane properties. These methods provide information necessary to evaluate the drug action. However, they have often the drawback that detailed molecular information is not accessible and explanations for some observed phenomena are lacking. Therefore, molecular dynamics (MD) simulations can be used, which provide a detailed atomistic understanding. Although MD is widely used, it is not completely understood to which extend results for drug-membrane interactions relate to experimental findings. Helicobacter pylori causes peptic ulcers and gastric cancer. Given its location in vivo, the absorption of antibiotics by the gastric mucosa is an important step of their pharmacokinetic properties. In fact, hampered absorption into deeper layers of the gastric mucosa and insufficient residence time in the stomach are important limitations of the current therapy. The gastric mucosa environment represents an extreme pH value of 1.2. Drug-membrane interactions under such extreme conditions were not considered in MD studies before. Here for the first time, these simulations were carried out and connected to experimental findings. MD simulations of DPPC membranes were performed, where pH 1.2 and pH 7.4 were mimicked through different protonation states of both the drugs (metronidazole and omeprazole) and the lipids. Umbrella sampling simulations were carried out in order to obtain the free energy profiles of the drugs, leading to the preferential location and the partition coefficients. Furthermore, drug influences on membrane phases were studied. In most cases good agreement between simulation and experimental results were found. Therefore, the simulations results could be evaluated and the detailed atomistic picture provided by MD lead to a better understanding of the experimental results. In the particular case of metronidazole, we have shown that the partition is higher at physiological pH than at pH 1.2. However, this partition may disturb the biophysical properties of the membrane (e.g., order). This effect depends on the location and orientation of the drug in the membrane and, ultimately, it can be related with toxicity.

Drug-membrane interactions at different pH values: Molecular dynamics simulations in combination with experimental techniques

251st National Meeting (2016)

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