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.

最近我们对癌变机制的理解取得了进展，这导致了新药物的发现和合成，这些药物可以在实验动物和人类中抑制肿瘤的发展。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在直接参与致癌作用的特定分子靶点上，基于结构的先导化合物设计和优化作为一个领域正在成熟。该项目的长期目标之一是使用基于靶标的方法来识别新的化学预防化合物，这些化合物将直接作为治疗药物或作为治疗的先导分子