Novel tool for linking drugs and phenotypes

连接药物和表型的新工具

• 批准号: 8834211
• 负责人: Klara O Felsovalyi
• 金额: $ 35万
• 依托单位: GENECENTRIX, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-10 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8834211
• 关键词: Address; Affinity; Algorithms; Biological Markers; Biology; Cataloging; Catalogs; Chemicals; Collection; Complex; Computer Analysis; Computing Methodologies; Data; Data Set; Databases; Detection; Development; Disease; Docking; Drug Approval; Drug Combinations; Drug Compounding; Drug Industry; Drug Targeting; Effectiveness; Fingerprint; Gene Expression; Genomics; Goals; Gold; Healthcare; Individual; International Classification of Diseases; Knowledge; Lead; Link; Maps; Marketing; Measures; Medicine; Methods; Modeling; Molecular; Molecular Profiling; Molecular Target; National Human Genome Research Institute; Outsourcing; Pathogenesis; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Probability; Process; Productivity; PubMed; Research; Research Personnel; Science; Staging; Statistical Models; Symptoms; Syndrome; System; Technology; Tissues; Weight; base; clinical phenotype; cost; cost effective; disease phenotype; drug candidate; drug development; drug discovery; drug mechanism; genome wide association study; human tissue; improved; novel; prototype; public health relevance; statistics; text searching; tool

DESCRIPTION (provided by applicant): Bringing new drugs to market is a lengthy and expensive endeavor. To increase the number of affordable new drugs available to consumers at reasonable costs, the efficiency of the drug development process must be greatly improved. We aim to develop a novel tool that addresses this challenge by rapid identification of drug targets and drug candidates for any given clinical phenotype utilizing our newly developed computational method. This method is based on a hypothesis that the tissue pattern of the expression of drug targets is essential for the unbiased matching of phenotypes to potential drugs. Matching complex molecular biomarkers of a disease to drugs thus depends on knowledge of the complete molecular signature (polypharmacologic fingerprint) of the drug or drug combination. Our approach is based on integration of large datasets from chemical and 'omics' databases and developing algorithms to link clinical phenotypes with drugs and drug-like chemicals. This is achieved by identifying the polypharmacologic profile of bioactive drugs and matching this drug-based profile to a phenotype-based tissue profile of a disease, which is derived from the computational analysis of 'omics' data. We have already developed and validated the 'drug' module of this system. Here we propose to (a) develop the 'phenotype' module, which will include the phenotype-tissue-target data via integration of clinical phenotypes, tissue-specific target expression, and GWAS and microarray data; (b) develop 'matching' algorithms for the modules that will build a direct link between drugs and clinical phenotypes as well as a ranking system for those matches; (c) validate this system using well-established clinical phenotypes and drugs for their treatment. When completed, the proposed research will result in a system that will allow users to instantly identify the ranked list of predicted drugs for any given clinical phenotype. Alternatively, it can be used to identify a list f phenotypes associated with any given drug/compound or drug/compound combination. This addresses a major challenge in the drug development process, improving the productivity and efficiency of the drug discovery phase, and it provides a useful and highly desired tool for the pharmaceutical industry and for academic research. Ultimately this technology will help in understanding the genomic contributions to the biology of disease and to accelerate the use of genomics to advance the science of medicine and the effectiveness of healthcare.

描述（由申请人提供）：将新药推向市场是一项漫长而昂贵的努力。为了增加消费者以合理价格获得的负担得起的新药的数量，必须大大提高药物开发过程的效率。我们的目标是开发一种新的工具，通过利用我们新开发的计算方法快速识别任何给定临床表型的药物靶点和候选药物来应对这一挑战。这种方法是基于一个假设，即药物靶点的表达的组织模式是必不可少的无偏匹配的表型潜在的药物。因此，将疾病的复杂分子生物标志物与药物相匹配取决于对药物或药物组合的完整分子特征（多药理学指纹）的了解。我们的方法是基于化学和“组学”数据库的大型数据集的整合，并开发算法将临床表型与药物和药物样化学物质联系起来。这是通过鉴定生物活性药物的多药理学特征并将该基于药物的特征与疾病的基于表型的组织特征相匹配来实现的，所述基于表型的组织特征源自"组学"数据的计算分析。我们已经开发并验证了该系统的"药物"模块。在这里，我们建议（a）开发"表型"模块，其将通过整合临床表型、组织特异性靶表达、GWAS和微阵列数据来包括表型-组织-靶数据;（B）开发用于模块的"匹配"算法，其将在药物和临床表型之间建立直接联系，以及用于这些匹配的排名系统;（c）利用已确定的临床表型和治疗药物验证这一系统。完成后，拟议的研究将产生一个系统，允许用户立即识别任何给定临床表型的预测药物的排名列表。或者，其可用于鉴定与任何给定药物/化合物或药物/化合物组合相关的表型列表。这解决了药物开发过程中的一个重大挑战，提高了药物发现阶段的生产力和效率，并为制药行业和学术研究提供了一个有用的和非常理想的工具。最终，这项技术将有助于理解基因组对疾病生物学的贡献，并加速基因组学的使用，以推进医学科学和医疗保健的有效性。