Structural Biology

结构生物学

• 批准号: 6938231
• 负责人: ANDREW D MESECAR
• 金额: $ 18.55万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6938231
• 关键词: X ray crystallography; androgen receptor; biological products; biotechnology; cancer prevention; carcinogenesis inhibitor; chemoprevention; drug design /synthesis /production; drug discovery /isolation; estrogen receptors; gene expression; high throughput technology; liquid chromatography mass spectrometry; nuclear receptors; pharmacokinetics; prostaglandin endoperoxide synthase; protein protein interaction; protein purification; protein structure; site directed mutagenesis; structural biology

Recent advances in our understanding of the mechanisms of carcinogenesis are leading to the discovery and synthesis of new drugs that can inhibit tumor development in both experimental animals and humans. The discovery and development of both natural and synthetic chemopreventive agents is rapidly advancing because screening methods are now focusing on specific molecular targets that are involved directly in carcinogenesis, and structure-based design and optimization of lead compounds is maturing as a field. One of the long-term objectives of this program proposal is to use target-based approaches to identify novel chemopreventive compounds that will serve either directly as therapeutic agents, or as lead molecules for the structure-based design and synthesis of potential therapeutic agents. To attain this objective, we propose a series of specific aims that have the unifying theme of investigating at the molecular level, the structural basis for chemopreventive activity of natural and synthetic compounds. Specifically, we propose to clone, express, purify, crystallize, and determine the x-ray structures of select molecular targets in complex with either new and/or existing chemopreventive compounds. Initial targets include those already under investigation by our program, i.e. cyclooxygenases 1 and 2 and estrogen receptors alpha and beta, as well as new targets including the Keap1/Nrf2 system, and the retinoid and androgen receptors. The threedimensional structures of active compounds, in complex with the protein targets will be determined and the structural information obtained will be used to help guide the synthetic efforts for the design of novel and more potent chemopreventive agents. In addition to the proposed studies on the macromolecular targets. This project will also serve partially as a core that will provide purified protein for bioassay-guided fractionation and compound identification. Finally, we will also determine the small molecule structures of natural and synthetic compounds.

我们对癌变机制的理解的最新进展是导致发现和合成新药，这些新药可以抑制实验动物和人类的肿瘤发展。天然和合成化学预防剂的发现和开发正在迅速发展，因为筛选方法现在集中在直接参与致癌作用的特定分子靶标上，基于结构的设计和铅化合物的优化正作为一个领域成熟。该计划提案的长期目标之一是使用基于目标的方法来识别新型化学预防化合物，这些化合物将直接用作治疗剂，或者作为铅分子作为铅分子 潜在治疗剂的基于结构的设计和合成。为了实现这一目标，我们提出了一系列特定目标，这些目标具有在分子水平上进行研究的统一主题，这是天然和合成化合物化学预防活性的结构基础。具体而言，我们建议用新的和/或现有的化学预防化合物克隆，表达，纯化，结晶并确定复合物中的精选分子靶标的X射线结构。最初的目标包括我们程序已经在研究的那些，即环氧合酶1和2和雌激素受体α和β，以及包括KEAP1/NRF2系统在内的新靶标，以及类维生素类和雄激素受体。将确定活性化合物的三级结构，与蛋白质靶标的复杂性，并将获得的结构信息用于指导设计新颖和更有效的化学预防剂的合成努力。此外 提出的关于大分子靶标的研究。该项目还将部分用作核心，该核心将提供纯化的蛋白质用于生物测定引导分级和化合物 鉴别。最后，我们还将确定天然和合成化合物的小分子结构。