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）：药物向特定的眼组织输送是一个主要挑战，因为药物摄取和眼部分布所需的因素仍然很大程度上不确定。 分子描述量越来越多地用于定义和建模药物的药理I药代动力学特性。 该提案通过确定药物上的特定分子描述符可用于将分子用于“引导”分子到其特定的眼靶组织，从而引入了一种新的眼药递送和分布方法。 这 基于我们的发现，即精选的分子属性I描述符似乎指导我们在我们的实验室中合成的多功能抗氧化剂（MFAO）的摄取和分布，该抗透镜，神经视网膜和大脑。 该提案旨在通过将研究扩展到包括父和单功能类似物在内的24种化合物，从而扩展使用6个MFOA的最初观察结果。 分子属性/描述符将使用分子操作环境（MOE）软件以及沃尔赛夫软件获得，该软件是专门设计用于在硅药代动力学特性中优化的。 这些将与成年大鼠眼睛以及大脑，肝脏，肾脏，肾脏和外围（Sciatic）神经的角膜，睫状体，晶状体，神经视网膜以及其余的后部段（RPE，脉络膜，巩膜）相关。 在体内定量结构活动关系（QSAR）模型中建立的相关性将通过随后评估从模型设计的测试化合物，然后在大鼠中合成和评估的测试化合物进行验证。 经过验证的模型不仅将使我们能够预测MFAO的组织摄取，而且还将建立一个模型，以根据其分子属性 /描述符来预测其他药物的组织摄取。