ROADMAP FOR DRUG DISCOVERY IN SMALL MOLECULE METABOLISM

小分子代谢药物发现路线图

基本信息

批准号：
8170555
负责人：
PATRICIA CLEMENT BABBITT
金额：
$ 1.79万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8170555
关键词：
Animal Model Bacteria Chemicals Collection Computer Retrieval of Information on Scientific Projects Database Databases Drug Delivery Systems Enzymes Funding Grant Human Institution Ligands Link Maps Metabolic Metabolism Methods Pharmaceutical Preparations Research Research Personnel Resources Route Source Therapeutic Toxic effect United States National Institutes of Health base drug discovery drug metabolism methicillin resistant Staphylococcus aureus novel pathogen small molecule

Animal Model Bacteria Chemicals Collection Computer Retrieval of Information on Scientific Projects Database Databases Drug Delivery Systems Enzymes Funding Grant Human Institution Ligands Link Maps Metabolic Metabolism Methods Pharmaceutical Preparations Research Research Personnel Resources Route Source Therapeutic Toxic effect United States National Institutes of Health base drug discovery drug metabolism methicillin resistant Staphylococcus aureus novel pathogen small molecule

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项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Small molecule metabolism is a tempting yet treacherous domain for drug discovery. Numerous drugs target metabolic enzymes in humans and bacteria, often mimicking their substrates, with both therapeutic and toxic effect. To provide a large-scale overview of the intersection between drugs and metabolism, we first group drugs and metabolites by their associated targets and enzymes, then create ligand-based set signatures to quantify their degree of difference in chemical space. This 'roadmap' illustrates what chemical space surrounding metabolism has been explored, where successful drugs have been found, and what novel territory remains. Using links between drug and metabolite sets, we predict the 'effect space' comprising a drug's likely metabolic targets. These links indicate potential toxicity, suggest routes of metabolism, and reveal drug polypharmacology. To aid other researchers in their drug discovery efforts, we have created an online resource of species-specific maps linking drugs to metabolism for 385 model organisms and pathogens in the BioCyc database collection. We have applied our method to select and then experimentally confirm novel drug targets in the rising pathogenic threat methicillin-resistant Staphylococcus aureus.

该副本是利用众多研究子项目之一由NIH/NCRR资助的中心赠款提供的资源。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构是对于中心，这不一定是调查员的机构。小分子代谢是一个诱人但危险的域名，可以发现药物发现。许多药物靶向人类和细菌中的代谢酶，通常会模仿其底物，并具有治疗和毒性作用。为了对药物与代谢之间的交集进行大规模的概述，我们首先通过其相关靶标和酶将药物和代谢物分组，然后创建基于配体的设定签名，以量化其化学空间差异的程度。该“路线图”说明了已经探索了新陈代谢的化学空间，发现了成功的药物以及留下了什么新型领土。使用药物和代谢物组之间的联系，我们预测包括药物可能代谢靶标的“效应空间”。这些联系表明潜在的毒性，暗示了代谢途径，并揭示了药物多药理学。为了帮助其他研究人员进行药物发现工作，我们创建了一个在线特定地图的在线资源，该物种特异性地图将药物与生物气体数据库收集中的385种模型生物和病原体的新陈代谢联系起来。我们已经应用了我们的方法来选择并实验确认在耐甲氧西林的抗葡萄球菌金黄色葡萄球菌中升高的新型药物靶标。