Structure-Function Relationships for Drug Reactivity in Lipid Membranes

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Recent work has demonstrated that small organic molecules possess unexpected reactivity with lipid membranes (doi: 10.1126/sciadv.aaz8598, Science Advances) and that this reactivity has functional consequences (doi: 10.1039/c8sc04831b, Chem. Sci.). Many of the factors that control this reactivity are poorly understood: mechanistic aspects of the reactivity, including the rate determining step, have not been characterised. Preliminary data have revealed that how a molecule "partitions into the membrane interface" is likely to be crucial in dictating reactivity: specifically, the orientation and depth of binding. This project will use a combination of reactivity and binding measurements on model organic molecules in liposomes to probe the factors that control reactivity. Molecular modelling at atomistic and coarse-grained levels will be used to understand how partitioning depth and orientation affect reactivity, and to model the transition state of the rate determining step. The combination of experimental data and modelling will ensure that the work is both robust and insightful. The outcomes will challenge current thinking in lipid chemistry and lead to significant academic impact and wider economic and societal impact. Lipids are present or used in numerous fields. These include, for example:materials chemistry (liposome stability in applications including emollients and drug delivery agents);pharmacology (adverse drug reactions, drug attrition and pharmacokinetics, plus novel routes for exploiting reactivity to cross the blood brain barrier);cell physiology and biochemistry (where lipid membranes encapsulate cells and organelles); and food chemistry (food processing and degradation).