Using Molecular Attributes to Predict Ocular Drug Distribution

利用分子属性预测眼部药物分布

• 批准号: 8821623
• 负责人: PETER F KADOR
• 金额: $ 18.81万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821623
• 关键词: Adult; Adverse effects; Alzheimer' s Disease; Antioxidants; Binding; Blood; Brain; Cataract; Choroid; Ciliary Body; Clinical; Computer Simulation; Computer software; Cornea; Descriptor; Development; Diagnostic; Disease; Drug Delivery Systems; Drug Kinetics; Drusen; Effectiveness; Endophthalmitis; Environment; Eye; Health; High Pressure Liquid Chromatography; Inflammation; Inflammatory; Injection of therapeutic agent; Iris; Iron; Kidney; Laboratories; Liver; Macular degeneration; Maps; Measures; Metals; Modeling; Molecular; Mono-S; Neural Retina; Outcome; Parents; Patients; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Physiologic Intraocular Pressure; Physiological; Play; Process; Property; Proteins; Quantitative Structure-Activity Relationship; Rattus; Retina; Retinal Detachment; Risk; Role; Scientist; Sclera; Structure; Structure of ciliary processes; Structure-Activity Relationship; Technology; Time; Tissues; Topical application; Zinc; age related; analog; base; compliance behavior; design; drug development; drug discovery; drug distribution; evaluation/testing; high risk; in vivo; insight; lens; model design; novel strategies; oxidative damage; prevent; protein complex; sciatic nerve; tool; uptake

DESCRIPTION (provided by applicant): Drug delivery to specific ocular tissues is a major challenge because the factors required for the uptake and ocular distribution of drugs remains largely undefined. Molecular descriptors are increasingly being used to define and model the pharmacological I pharmacokinetic properties of drugs. This proposal introduces a new approach to ocular drug delivery and distribution by establishing that specific molecular descriptors on a drug can be used to "guide" a molecule to its specific ocular target tissue. This is based on our finding that select molecular attributes I descriptors appear to guide the uptake and distribution of orally administered multifunctional antioxidants (MFAOs) synthesized in our laboratory into the lens, neural retina, and brain. This proposal seeks to expand on this initial observation with 6 MFOAs by expanding the study to 24 compounds that include the parent and mono- functional analogs. Molecular attributes/descriptors will be obtained using Molecular Operating Environment (MOE) software as well as Volsurf software that is especially designed for optimizing in silico pharmacokinetic properties. These will be correlated with drug levels obtained in the cornea, iris/ciliary body, lens, neural retina and the remaining posterior segment (RPE, choroid, sclera) of adult rat eyes as well as brain, liver, kidney, and peripheral (sciatic) nerve. The correlations established in the in vivo quantitative structure activity relationship (QSAR) model will be validated by the subsequent evaluation of test compounds that are designed from the model and then synthesized and evaluated in rats. The validated model will not only allow us to predict the tissue uptake of MFAOs, but will also establish a model for predicting the tissue uptake of other drugs based on their molecular attributes / descriptors.

描述（由申请人提供）：由于药物摄取和眼部分布所需的因素在很大程度上仍不确定，因此将药物递送至特定眼部组织是一项重大挑战。 分子描述符越来越多地用于定义和建模药物的药理学/药代动力学特性。 该提案通过建立药物上的特定分子描述符可用于将分子“引导”至其特定的眼部靶组织来引入眼部药物递送和分布的新方法。 这 是基于我们的发现，选择的分子属性I描述符似乎引导摄取和分布的口服给药的多功能抗氧化剂（MFAOs）在我们的实验室合成到透镜，神经视网膜，和大脑。 该提案旨在通过将研究扩展到包括母体和单功能类似物的24种化合物来扩展6种MFOA的初步观察结果。 将使用Molecular Operating Environment（莫伊）软件以及Volsurf软件（专为优化计算机模拟药代动力学特性而设计）获得分子属性/描述符。 这些将与成年大鼠眼的角膜、虹膜/睫状体、透镜、神经视网膜和剩余后段（RPE、脉络膜、巩膜）以及脑、肝、肾和外周（坐骨）神经中获得的药物水平相关。 体内定量构效关系（QSAR）模型中建立的相关性将通过随后评价根据模型设计的供试化合物进行验证，然后在大鼠中合成和评价。 经验证的模型不仅允许我们预测MFAO的组织摄取，而且还将建立基于其分子属性/描述符预测其他药物的组织摄取的模型。