Pharmaceuticals and Physics: Drugs and Membranes

Abstract

Active pharmaceutical ingredients (APIs) are usually designed to stick to some target in the body. This target is typically a protein, and the drug is supposed to change how that protein functions. However, side-effects are an inevitable consequence of introducing foreign molecules, such as drugs, into the body, since drug molecules are more than likely to interact non-specifically with other cellular structures, such as lipid membranes. The membrane is a highly relevant structure, as it is a ubiquitous biological interface, that defines the surface of cells and also internal cell components. The membrane is more than just a wall, as it plays an important role in controlling processes on the cell surface. Drug molecules have been shown to interact with membranes by non-specific Van- der-Waals interactions. However, not enough is known regarding how drugs influence the membrane structure, or how to design drugs that minimize membrane related side-effects. X-ray and neutron scattering techniques, as well as Molecular Dynamics simulations, are capable of providing the molecular details. Synthetic membranes may be prepared with any lipid or drug composition and are tools for modelling interactions. In this thesis, I used scattering experiments on synthetic systems to study drug-membrane interactions on the atomic and molecular scales, in order to understand how the drugs influence membrane properties. I optimized the use of scattering techniques for determining drug effects on membranes. From my research, there are two main insights. 1. Drug-membrane interactions disrupt local membrane structure. This is based on a case study of aspirin where, over three studies, I presented evidence that the aspirin disrupts cholesterol in the lipid membrane. X-ray and neutron scattering techniques, in combination with Molecular Dynamics simulations were used to determine that aspirin’s impacts are the result of locallized disruptions to the lipid structure. 2. I also present three case studies for how the properties of the membrane itself play a role in shaping the drug interaction. Biophysical properties, such as hydration and stiffness, tune how the drug interacts with the membrane. X-ray and neutron scattering are required to generate the molecular picture for why the specific biophysical membrane properties are relevant. The set of interactions discovered here are not, by any means, exhaustive. However, the work demonstrates that molecular level details reveal unique insights on drug-membrane interactions, details that may be useful when designing drugs and mitigating their side effects.