ROADMAP FOR DRUG DISCOVERY IN SMALL MOLECULE METABOLISM

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 小分子代谢是药物发现的一个诱人但危险的领域。许多药物靶向人体和细菌中的代谢酶，通常模拟其底物，具有治疗和毒性作用。为了提供药物和代谢之间的交叉点的大规模概述，我们首先根据药物和代谢物的相关靶标和酶对其进行分组，然后创建基于配体的集合签名来量化它们在化学空间中的差异程度。这个“路线图”说明了围绕代谢的化学空间已经被探索，在哪里发现了成功的药物，以及还有什么新的领域。使用药物和代谢物集之间的联系，我们预测的“效应空间”，包括药物的可能的代谢目标。这些联系表明了潜在的毒性，提示了代谢途径，并揭示了药物的多药理学。为了帮助其他研究人员进行药物发现工作，我们创建了一个将药物与BioCyc数据库中385种模式生物和病原体的代谢联系起来的物种特异性地图的在线资源。我们已经应用我们的方法来选择，然后在实验中确认新的药物靶点在不断上升的致病性威胁耐甲氧西林金黄色葡萄球菌。

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.