Structure-Function Relationships for Drug Reactivity in Lipid Membranes

最近的研究表明，小有机分子与脂质膜具有意想不到的反应性。aaz8598, Science Advances)，并且这种反应性具有功能后果(doi: 10.1039/c8sc04831b, Chem。Sci)。控制这种反应性的许多因素尚不清楚：反应性的机理方面，包括速率决定步骤，尚未被描述。初步数据显示，分子如何“分裂成膜界面”可能是决定反应性的关键：具体来说，是结合的方向和深度。本项目将结合对脂质体中模型有机分子的反应性和结合测量来探测控制反应性的因素。原子和粗粒度水平的分子模型将用于理解分配深度和取向如何影响反应性，并模拟速率决定步骤的过渡状态。实验数据和模型的结合将确保这项工作既稳健又富有洞察力。研究结果将挑战目前脂质化学的思维，并产生重大的学术影响和更广泛的经济和社会影响。脂质存在或应用于许多领域。这些包括，例如：材料化学（包括润肤剂和药物递送剂在内的应用中的脂质体稳定性）；药理学（药物不良反应、药物损耗和药代动力学，以及利用反应性穿越血脑屏障的新途径）；细胞生理学和生物化学（脂质膜包裹细胞和细胞器）；食品化学（食品加工和降解）。

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).