Structure-Function Relationships for Drug Reactivity in Lipid Membranes

最近的工作已经证明，小有机分子具有与脂质膜的出乎意料的反应性（doi：10.1126/sciadv.aaz8598，Science Advances），并且这种反应性具有功能性后果（doi：10.1039/c8 sc 04831 b，Chem. Sci.）。控制这种反应性的许多因素知之甚少：反应性的机械方面，包括速率决定步骤，尚未被表征。初步数据显示，分子如何“分配到膜界面”可能是决定反应性的关键：特别是结合的方向和深度。该项目将使用反应性和结合测量脂质体中的模型有机分子的组合来探测控制反应性的因素。在原子和粗粒度水平的分子建模将被用来了解分区深度和取向如何影响反应性，并模拟的速率决定步骤的过渡态。实验数据和建模的结合将确保工作既稳健又有洞察力。这些成果将挑战脂质化学的当前思想，并产生重大的学术影响和更广泛的经济和社会影响。脂质存在于或用于许多领域。这些包括，例如：材料化学（脂质体在包括润肤剂和药物递送剂在内的应用中的稳定性）;药理学（药物不良反应，药物磨损和药代动力学，以及利用反应性穿过血脑屏障的新途径）;细胞生理学和生物化学（其中脂质膜包裹细胞和细胞器）;和食品化学（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).