Structural Biology

我们对致癌机制的理解的最新进展导致了可以抑制实验动物和人类肿瘤发展的新药的发现和合成。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标上，并且基于结构的先导化合物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点的方法来鉴定新的化学预防化合物，这些化合物将直接作为治疗剂，或作为用于治疗癌症的先导分子。 基于结构的潜在治疗剂的设计和合成。为了实现这一目标，我们提出了一系列的具体目标，有统一的主题调查在分子水平上，天然和合成化合物的化学预防活性的结构基础。具体而言，我们建议克隆，表达，纯化，结晶，并确定X-射线结构的选择分子靶点与新的和/或现有的化学预防化合物的复合物。最初的靶点包括我们项目已经在研究的靶点，即环加氧酶1和2以及雌激素受体α和β，以及新的靶点，包括Keap 1/Nrf 2系统，以及类维生素A和雄激素受体。活性化合物的三维结构，在复杂的蛋白质目标将被确定和获得的结构信息将被用来帮助指导设计新的和更有效的化学预防剂的合成努力。除了 对大分子靶点的拟议研究。该项目还将部分作为核心，为生物测定指导的分离和复合提供纯化蛋白质。 识别.最后，我们还将确定天然和合成化合物的小分子结构。

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.