Identification and Validation of Targets of Phenotypic High Throughput Screening

描述（由申请人提供）：南美锥虫病表型高重复率筛选命中目标的鉴定和验证项目摘要拉丁美洲近1000万人感染了真核寄生虫克氏锥虫，这是南美锥虫病的病原体。世界卫生组织（世卫组织）将恰加斯病列为一种被忽视的热带疾病，但恰加斯病在美国正被视为一种新出现的感染，估计有30万人可能受到感染。不幸的是，没有FDA批准的治疗恰加斯病的方法，在美国以外使用的治疗方法具有毒副作用。迫切需要新的南美锥虫病疗法。然而，很少有有前途的候选药物已经进入临床，现有的药物开发管道缺乏目标多样性。为了促进和催化对查加斯病的新疗法的鉴定，药物发现合作组织和SRI提出开发和验证一种新的组合计算系统生物学方法，该方法预测表型筛选命中的代谢酶靶标。拟议的方法将开发和验证恰加斯病（第一阶段），并扩大到开发一个原型研究工具，以支持目标预测和验证多种疾病的表型筛选命中（第二阶段）。更具体地说，在I期，CDD和SRI将（i）开发一种新的方法，该方法使用计算方法来鉴定通过高通量筛选（HTS）命中和代谢途径的生物信息学分析在结构上模拟的寄生虫代谢物，以最终预测命中的靶点，（ii）将该方法应用于从针对锥虫病测试的300，000多个化合物编译的HTS命中。cruzi在文献和公共HTS数据集汇编CDD的公共数据库，和（iii）进行初步实验，以验证预测的目标化合物对。在第二阶段，CDD和SRI将对预测进行更广泛的实验验证，并将药物靶点预测方法应用于其他被忽视的热带疾病，以证明该方法的更广泛用途。最终，CDD将开发一个软件模块，使工作流程自动化，并促进CDD软件平台与外部生物信息学数据库（如SRI BioCyc数据库）之间的生物信息学和化学数据共享。该模块是一套提出的模块之一，涉及药物发现过程的各个方面，这些模块将与CDD现有的药物发现软件平台沿着集成和商业化。

DESCRIPTION (provided by applicant): Identification and Validation of Targets of Phenotypic High Throughput Screening Hits for Chagas Disease Project Summary Nearly 10 million people in Latin America are infected with the eukaryotic parasite Trypanosoma cruzi, the causative agent of Chagas disease. The World Health Organization (WHO) classifies Chagas disease as a neglected tropical disease, but Chagas disease is gaining recognition as an emerging infection in the United States where an estimated 300,000 people may be infected. Unfortunately, there are no FDA approved treatments for Chagas disease and treatments used outside the U.S. have toxic side effects. New therapeutics for Chagas disease are desperately needed. However, few promising drug candidates have advanced to the clinic and the existing drug development pipeline lacks target diversity. In order to facilitate and catalyze the identification of novel therapeutics for Chagas disease, Collaborative Drug Discovery and SRI propose to develop and validate a new combined computational- systems biology approach that predicts metabolic enzyme targets of phenotypic screening hits. The proposed methodology will be developed and validated for Chagas disease (Phase I) and expanded to develop a prototype research tool to support target prediction and validation for phenotypic screening hits from multiple diseases (Phase II). More specifically, in Phase I CDD and SRI will (i) develop a novel approach that using computational methods to identify parasite metabolites structurally mimicked by high throughput screening (HTS) hits and bioinformatics analyses of metabolic pathways to ultimately predict the target of hits, (ii) apply the approach to HTS hits for Chagas disease compiled from over 300,000 compounds tested against T. cruzi in the literature and public HTS datasets compiled in CDD's public database, and (iii) conduct preliminary experiments to validate predicted target-compound pairs. In Phase II, CDD and SRI will conduct more extensive experimental validation of predictions and apply the drug target prediction methodologies to additional neglected tropical diseases to demonstrate the broader utility of the approach. Ultimately, CDD will develop a software module that automates workflow and facilitates sharing of bioinformatics and chemiformatic data between CDD's software platform and external bioinformatics databases such as the SRI BioCyc database. This module is one of a suite of proposed modules addressing aspects of the drug discovery process that will be integrated and commercialized along with CDD's existing drug discovery software platform.