Chemical Address Tags: A Cheminformatics & Image Data Management and Analysis Plan - Equipment Supplement

描述（由申请人提供）：药物不良反应（adr）是美国住院和死亡的主要原因之一。不良反应通常与不良的药物生物利用度或生物分布有关。因此，可以通过优化药物从系统、器官水平到微观、细胞水平的转运特性来预防adr。为了提高进入临床试验的药物质量，新一代显微成像仪器被称为“高含量筛选”或“HCS”系统已经开发出来。HCS仪器可以提供临床前、基于人类细胞的数据，以补充预测毒理学测试的动物研究。作为一个高通量平台，HCS系统可用于筛选生理相关分析中的大量小分子。现在的挑战是推进HCS技术，以促进低毒性候选药物的开发，提高临床成功率。为了应对这一挑战，我们建议开发一种化学信息学和图像数据管理和分析计划来研究活细胞中小分子的亚细胞定位。受机器视觉方法的启发，目前被用作分析全基因组范围内蛋白质亚细胞分布的工具（“定位蛋白质组学”），我们提出机器视觉也可以被用作分析具有可检测光学特征的小分子候选药物分布的工具。与蛋白质定位由信号肽编码类似，我们假设亚细胞小分子定位由在小分子化学结构中发现的“化学地址标签”编码。为了验证这一假设，我们计划：1)开发自动化，图像分析和化学信息学工具，以客观，定量和高通量的方式对化学地址标签进行逆向工程；2)开发和比较两种定量的机器视觉方法来检测细胞器靶向分子的运输特性；3)演示化学信息学驱动的图像数据管理和分析计划如何影响药物先导优化工作。

DESCRIPTION (provided by applicant): Adverse drug reactions (ADRs) are one of the leading causes of hospitalization and death in the United States. ADRs are often associated with unfavorable drug bioavailability or biodistribution profiles. Thus, ADRs could be prevented by optimizing drug transport properties from the systemic, organ level down to the microscopic, cellular level. To improve the quality of drugs entering clinical trials, a new generation of microscopic imaging instruments known as "high content screening" or "HCS" systems has been developed. HCS instruments can provide preclinical, human cell-based data to complement animal studies in predictive toxicology testing. As a high-throughput platform, HCS systems can be used to screen large collections of small molecules in physiologically-relevant assays. Now the challenge is to advance HCS technology to facilitate development of less toxic drug candidates with improved clinical success rates. To face this challenge, we propose to develop a cheminformatics and image data management and analysis plan to study the subcellular localization of small molecules in living cells. Inspired by machine vision approaches currently being used as a tool to analyze the subcellular distribution of proteins on a genome-wide scale ("location proteomics"), we propose that machine vision could also be adopted as a tool to analyze the distribution of small molecule drug candidates possessing a detectable optical signature. In analogy to how protein location is encoded by signal peptides, we hypothesize that subcellular small molecule localization is encoded by "Chemical Address Tags" to be discovered within the chemical structure of small molecules. To test this hypothesis, we plan to: 1) Develop automated, image analysis and cheminformatics tools to reverse-engineer Chemical Address Tags in an objective, quantitative and high-throughput manner; 2) Develop and compare two quantitative, machine vision approaches to assay the transport properties of organelle-targeting molecules; 3) Demonstrate how a cheminformatics-driven, image data management and analysis plan can impact a drug lead optimization effort.