SYSTEMS BIOLOGY APPROACH TO COMBINATORIAL DRUG TARGETING

组合药物靶向的系统生物学方法

• 批准号: 7723261
• 负责人: AVIJIT GHOSH
• 金额: $ 0.05万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7723261
• 关键词: Affinity; Binding; Calcium; Cell physiology; Complex; Computer Retrieval of Information on Scientific Projects Database; Computer Simulation; Dose; Drug Delivery Systems; Drug Industry; Funding; Grant; Guanine; Guanine Nucleotide Exchange Factors; Institution; Investigation; Mitogen-Activated Protein Kinases; Modeling; Pathway interactions; Pharmaceutical Preparations; Process; Proteins; Research; Research Personnel; Resources; Signal Transduction Pathway; Source; Specific qualifier value; Specificity; Systems Biology; Time; United States National Institutes of Health; Work; analog; anticancer research; antitumor agent; combinatorial; inhibitor/antagonist; novel; response; tumorigenesis; virtual

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. In silico models of signal transduction pathways have been highly successful in describing, quantitatively, how complex protein networks govern overall cell function. We propose to analyze a recently developed model of oncogenesis in the Mitogen Activated Protein Kinase (MAPK) signal transduction pathway, to understand how drugs targeting the MAPK pathway can act synergistically to enhance efficacy. We have already developed quantitative ranking of putative targets that inhibit the transformation process where each drug acts alone. The inhibitor, a virtual drug, is constructed by specifying its parameters: initial concentration and binding affinity kd. Many of the targets found by this analysis have inhibitors that are currently under investigation. In addition, several novel targets not previously investigated have been found. Of the thirteen targets, Ras, Guanine Exchange Factor (GEF), and Raf, show the highest potential. In addition, the analysis finds that certain calcium blockers may have much potential as anti-tumor agents, functioning at much lower concentrations but requiring higher specificity. To expand this work to investigate multiple targets requires extensive computational time not available in our lab. Investigating, dose-dose response curves has a strong experimental analogue and the extension of systems biology to investigate such responses in parallel has implications in both the pharmaceutical industry and cancer research. A starter grant for a small amount of CPU time at PSC would greatly enhance the time needed to do this analysis.

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。列出的机构为 研究中心，而研究中心不一定是研究者所在的机构。 信号转导通路的计算机模型在定量描述复杂的蛋白质网络如何控制整体细胞功能方面非常成功。我们建议分析最近开发的有丝分裂原活化蛋白激酶（MAPK）信号转导通路中的肿瘤发生模型，以了解靶向MAPK通路的药物如何协同作用以提高疗效。我们已经开发了定量排名的假定目标，抑制转化过程中，每种药物单独作用。通过指定其参数：初始浓度和结合亲和力kd来构造抑制剂，即虚拟药物。这项分析发现的许多靶点都有抑制剂，目前正在研究中。此外，还发现了一些以前没有研究过的新靶点，其中Ras、鸟嘌呤交换因子（GEF）和Raf是最有潜力的靶点。此外，分析发现，某些钙阻滞剂可能具有很大的抗肿瘤潜力，在低得多的浓度下发挥作用，但需要更高的特异性。为了扩展这项工作，以研究多个目标，需要大量的计算时间，这在我们的实验室是不可用的。研究剂量-剂量反应曲线具有很强的实验相似性，并且系统生物学的扩展并行研究此类反应对制药工业和癌症研究都有影响。为PSC提供少量CPU时间的启动补助金将大大增加进行此分析所需的时间。