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.

我们对致癌机制理解的最新进展正在导致新药物的发现和合成，这些新药物可以抑制实验动物和人类肿瘤的发展。天然和合成化学预防剂的发现和开发正在迅速推进，因为筛选方法现在集中于直接参与致癌作用的特定分子靶点，并且先导化合物的基于结构的设计和优化作为一个领域正在成熟。该计划提案的长期目标之一是使用基于靶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，或作为先导分子 潜在治疗剂的基于结构的设计和合成。为了实现这一目标，我们提出了一系列具体目标，其统一主题是在分子水平上进行研究，即天然和合成化合物化学预防活性的结构基础。具体来说，我们建议克隆、表达、纯化、结晶和确定与新的和/或现有的化学预防化合物复合的选定分子靶标的X射线结构。最初的目标包括我们的项目已经在研究的目标，即环氧合酶 1 和 2 以及雌激素受体 α 和 β，以及包括 Keap1/Nrf2 系统、类维生素A 和雄激素受体在内的新目标。将确定与蛋白质靶标复合的活性化合物的三维结构，获得的结构信息将用于帮助指导设计新型和更有效的化学预防剂的合成工作。此外 拟议的大分子靶点研究。该项目还将部分作为核心，为生物测定引导的分级分离和化合物提供纯化的蛋白质 鉴别。最后，我们还将确定天然和合成化合物的小分子结构。