FLEXIBLE LIGAND DOCKING FOR DRUG DESIGN II

用于药物设计 II 的灵活配体对接

• 批准号: 6121989
• 负责人: RICHARD GILLILAN
• 金额: $ 1.8万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6121989
• 关键词: AIDS; biological products; biomedical resource; biotechnology; computers; gene therapy; immunology; infection; inflammation; lymphatic system; plants; proteins; structural biology; technology /technique; virus

Rapamycin is the trivial name of an extraordinary natural product produced by a soil micro-organism, and it was first discovered through its ability to halt fungal growth. It soon became clear that antifungal activity was only one activity of rapamycin. It has been most thoroughly investigated as an immunosuppressive agent and is undergoing clinical trials as an anticancer agent. Most small molecules bind to and inhibit a single large molecule--HIV protease inhibitors inhibit the enzyme HIV protease, aspirin and ibuprofen (the active ingredient in Advil and Nuprin) block cyclooxygenase, and so on. Rapamycin controls biological processes in a different way by binding two large molecules together. About five years ago we became involved in studying the atomic details of how rapamycin works by studying the structure of rapamycin bound to one of its targets, and a year ago we completed the picture by using X-ray diffraction to define the structure of rapamycin simultaneously binding two proteins together. These studies not only showed how rapamycin works, they also showed the atomic structures of the two previously undefined proteins that rapamycin binds to. Several investigators, particularly Stuart Schreiber at Harvard and Jerry Crabtree at Stanford, soon realized that rapamycin's ability to bind two proteins together was the key to controlling a wide variety of biological processes. To understand the implications of a small molecule binding two large molecules together, a bit of background is needed. Many biological processes are controlled by having one molecule bring two other together. For example, human growth hormone brings two human growth hormone receptors together, and the signal for a growth starts when the two receptors are brought together. What rapamycin does is the small molecule analog of this joining process. Rapamycin has a molecular weight of around 1000 daltons and can pass through cell membranes. Growth hormone, for example, has a molecular weight of 22,000 daltons and cannot pass through cell membranes. Together with our collaborators we're designing and studying a series of rapamcyin analogs as well as analogs of the two proteins they bind together. We envision that these constructs will be useful in a variety of ways, and perhaps the most important will be gene therapy. Problems in gene therapy can be broken down into two main issues: introducing the genes needed and controlling the introduced genes. How can genes be controlled? A typical method is through the use of 'transcription factors' or proteins that tell a particular stretch of DNA that its instructions should be transcribed into messenger RNA. Transcription factors have two domains called the DNA binding domain and the activation domain. Both the binding and activation domain must be engaged with DNA for the gene to be expressed; if only one domain is engaged, little happens. Rapamycin and rapamycin analogs have been used to bring together binding and activation domains and thereby control gene expression. Our colleagues at ARIAD Pharmaceuticals have engineered mice in which the gene for human growth hormone has been introduced and controlled with rapamycin. Rapamycin turns the gene on, and withdrawal of rapamcyin shuts the gene down.

雷帕霉素是一种非凡的天然产物的俗名 它是由土壤微生物产生的， 阻止真菌生长的能力。 很快就清楚了， 抗真菌活性是雷帕霉素的唯一活性。 已经 最彻底的研究作为免疫抑制剂， 作为一种抗癌药物正在进行临床试验。 大多数小 分子结合并抑制单个大分子--HIV蛋白酶 抑制剂抑制酶HIV蛋白酶，阿司匹林和布洛芬（ Advil和Nuprin中的活性成分）阻断环氧合酶， 吧 雷帕霉素以不同的方式控制生物过程， 将两个大分子结合在一起 大约五年前， 参与研究雷帕霉素的原子细节， 研究雷帕霉素与其靶点之一结合的结构， 一年前，我们用X射线衍射确定了 雷帕霉素同时结合两种蛋白质的结构 一起 这些研究不仅展示了雷帕霉素的作用机制， 还显示了两个以前未定义的原子结构 与雷帕霉素结合的蛋白质 一些调查人员，特别是 哈佛的斯图尔特·施赖伯和斯坦福大学的杰里·克拉布特里，很快 意识到雷帕霉素将两种蛋白质结合在一起的能力， 控制各种生物过程的关键。 到 理解一个小分子结合两个大分子的含义， 分子在一起，需要一点背景。 许多生物 过程是由一个分子带着另外两个分子 一起 例如，人类生长激素带来两种人类生长 激素受体结合在一起，生长的信号开始于 两个受体结合在一起。 雷帕霉素的作用是 这种连接过程的小分子类似物。 雷帕霉素具有 分子量约为1000道尔顿，可以通过细胞 膜。 例如，生长激素的分子量为 22，000道尔顿，不能穿过细胞膜。 连同 我们的合作者正在设计和研究一系列的rapamcyin 类似物以及它们结合在一起的两种蛋白质的类似物。 我们 设想这些构建体将以多种方式有用， 也许最重要的是基因治疗。 基因问题 治疗可以分为两个主要问题： 所需的基因和控制引入的基因。 基因怎么可能 控制？ 一个典型的方法是通过使用'转录 因子或蛋白质告诉特定的DNA片段， 指令应该被转录成信使RNA。 转录 因子有两个结构域，称为DNA结合结构域和 激活域 结合域和激活域都必须是 与基因表达的DNA接合;如果只有一个结构域， 订婚了，没什么事。 雷帕霉素和雷帕霉素类似物已经被广泛应用。 用于将结合和激活结构域结合在一起， 控制基因表达。 我们ARIAD制药公司的同事 人类生长激素基因的基因工程小鼠， 引入并用雷帕霉素控制。 雷帕霉素将基因 而rapamcyin的退出会关闭该基因。