High Throughput Membrane-Water Partition Coefficients

高通量膜-水分配系数

• 批准号: 6992526
• 负责人: George E Wright
• 金额: $ 25.54万
• 依托单位: GLSYNTHESIS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6992526
• 关键词: cell membrane; drug screening /evaluation; fluorescence; fluorescence spectrometry; high throughput technology; lipid bilayer membrane; mathematics; pharmacokinetics; technology /technique development; vesicle /vacuole; water; cell membrane; drug screening /evaluation; fluorescence; fluorescence spectrometry; high throughput technology; lipid bilayer membrane; mathematics; pharmacokinetics; technology /technique development; vesicle /vacuole; water

DESCRIPTION (provided by applicant): A key molecular property used for drug screening and design is the partition coefficient, measured by partitioning between an organic solvent and water, but more commonly calculated with algorithms based on octanol:water-derived hydrophobicity constants. However, it is the membrane:water partition coefficient that is more relevant to partitioning of drugs into cell membranes. In this project we propose to exploit Fluorosome Technology to efficiently determine true membrane:water partition coefficients of drugs. "Fluorosomes-intra" are fluorescently labeled membrane lipid bilayer vesicles that measure drug entry rates into the membrane. By varying the concentrations of both test drug and lipid bilayer, and analysis of data by equilibrium or kinetic algorithms, we will establish a simple, rapid partition coefficient assay with membranes containing lipids that exist in cell membranes. The assay will .be applicable to a wide range of molecules using standard spectrofluorimeters, and can be adapted to multiwell plate formats and robotics. The specific aims are: to develop the Fluorosome-intra assay conditions and mathematical data analysis methods for the measurement of membrane:water partition coefficients of drugs; to optimize the Fluorosome-intra technique for the routine measurement of membrane:water partition coefficients, and; to validate the results of Fluorosome-intra in comparison with published values of membrane:water partition coefficients of known drugs. We will acquire partition coefficients of an expanded set of test drugs with Fluorosome-intra for comparison and correlation with published results obtained by other techniques. Fluorosome-intra methodology has the capacity to greatly enhance our ability to determine and understand the partitioning of drugs and other small molecules between water and biomembranes. This project seeks to exploit features of the technique that will extend the tools available to the medicinal chemist and drug discovery scientist, and to take advantage of the high-throughput capacity of the technique. The implementation of the Fluorosome Technique to the acquisition of membrane:water partition coefficients will thus greatly facilitate drug discovery.

描述（由申请人提供）：用于药物筛查和设计的关键分子特性是分配系数，通过在有机溶剂和水之间进行分配来测量，但更常见地使用基于辛醇的算法计算出来：水源性的疏水性常数。但是，是膜：水分系数与将药物分配到细胞膜中更相关。在这个项目中，我们建议利用荧光体技术有效确定真实膜：药物的水分系数。 “荧光体 - 内部”是荧光标记的膜脂质双层囊泡，可测量进入膜的药物进入速率。通过改变测试药物和脂质双层的浓度，以及通过平衡或动力学算法对数据进行分析，我们将使用含有细胞膜中存在的脂质的膜的简单快速分配系数测定。该测定法将使用标准谱荧光仪适用于各种分子，并且可以适用于多韦尔板格式和机器人技术。具体目的是：开发荧光体内部测定条件和膜测量的数学数据分析方法：药物的水分分配系数；为了优化膜体的荧光体 - 内置技术，以进行膜的常规测量：水分配系数，并且；与已知药物的水分配系数相比，验证荧光体内在的结果。我们将获取具有荧光体内置的一组扩展的测试药物组的分区系数，以比较和相关性与其他技术获得的已发表结果。荧光体内在方法论能够极大地增强我们确定和理解水与生物膜之间的药物和其他小分子分配的能力。该项目旨在利用该技术的特征，以扩展医疗化学家和药物发现科学家可用的工具，并利用该技术的高通量能力。荧光体技术的实施以获取膜：水分配系数将极大地促进药物发现。