Biological membranes are crucial to the life of the cell as they perform essential functions. They enclose the cell, define its boundaries and compartmentalize it. By being selectively permeable, they regulate the passage of substances into and out of cells, while at the same time they are involved in signal transduction. In this poster, several aspects of the structure and dynamics of biomembranes as well as methodologies for targeting specific membrane interfaces for developing novel drug candidates and drug delivery systems, will be presented. Signal transduction is largely controlled by proteins embedded in or associated with membranes, which in turn are also regulated by signaling entities integral to the cell membrane such as lipid rafts. To shed light on the mechanism of the promotion of lipid rafts in eukaryotic plasma membranes and their dependence on the sterol component, we have investigated the effects of specific sterols (cholesterol, ergosterol, lanosterol) on the physical properties of membranes using Molecular Dynamics (MD) simulations. The cell membrane is often the first barrier that drugs encounter before reaching their pharmacological target. Therefore, we investigated drug-membrane interactions with MD simulations and NMR spectroscopy focusing on the modifications of membrane biophysical properties induced by drugs, which is a crucial aspect for the future design of novel drugs targeting membrane proteins. As membrane proteins and in particular ion channels may be challenging to target with small molecule inhibitors, we established a protocol that utilizes free energy perturbation (FEP)/MD calculations of relative binding free energies and desolvation free energy penalties to leave the aqueous phase and bind to a membrane protein. Finally, we discuss targeting the membrane-protein Interface with small molecule inhibitors using a variety of computational and experimental methodologies and strategies for efficiently monitoring the translocation of drug delivery systems across biological membranes.

Targeting membrane interfaces for computer-aided drug design and drug delivery applications

248th National Meeting (2014)

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