Reactivity and Dynamics of Enediyne Natural Products

描述（由申请人提供）：这项拟议研究的目标是使用先进的计算方法来全面了解天然产物烯二炔家族的DNA切割机制。这一信息将指导实验工作者合成对肿瘤细胞更具选择性、对健康细胞毒性更小的烯二炔药物。目前，人们普遍认为天然产物中的烯二炔环会环化，从而产生一种从DNA主链中提取氢的活性双自由基。然而，还有其他的可能性。最近的实验证据表明，在生物条件下，烯二炔可以转化为高细胞毒性的醌或者，环化和氢原子的抽离可以协调一致，而不形成双自由基中间体如果正确的话，这种机制将迫使药物设计者从根本上改变他们的合成策略。我们将使用结合高级电子结构理论和低级半经验或分子力学方法的计算方法来精确模拟天然产物烯二炔。我们对这个项目有几个明确的目标。我们的第一个假设是，烯二炔在其弹头的环化过程中通过一种协调一致的机制从DNA中提取氢。我们的第二个假设是，附着在烯二酶片段上的糖负责将天然产物与DNA接触。我们将通过获得天然产物的环化和氢提取的可能途径的能量分布来验证第一个假设。然后，我们将确定分子的哪些部分对于第一步中发现的较低反应途径是必不可少的。第二个假设将通过开发适合与AMBER8一起使用的烯二炔类天然产物的参数来验证。8.然后，我们将运行分子动力学模拟，以显示烯二炔糖对DNA识别过程的影响。

DESCRIPTION (provided by applicant): The goal of this proposed research is to use advanced computational methods to gain a thorough understanding of the mechanism of DNA cleavage by the enediyne family of natural products. This information will guide efforts by experimentalists to synthesize enediyne drugs that are more selective towards tumor cells, and less toxic towards healthy cells. Currently, synthetic efforts are directed by the commonly accepted assumption that the enediyne rings in the natural products cyclize to generate a reactive diradical species that abstracts hydrogen from the DNA backbone. 1-5 However, there are other possibilities. Recent experimental evidence has shown that enediynes can be converted to highly cytotoxic quinones under biological conditions.6 Alternatively, the cyclization and hydrogen atom abstraction could be concerted, without the formation of a diradical intermediate.7 If correct, such mechanisms would force drug designers to radically alter their synthetic strategies. We will use computational methods that integrate high-level electronic structure theory and low-level semiempirical or molecular mechanics methods to accurately model the natural product enediynes. We have several explicit goals for this project. Our first working hypothesis is that enediynes extract hydrogen from DNA through a concerted mechanism during the cyclization of their warheads. Our second working hypothesis is that the sugars attached to the enediyne moiety are responsible for bringing the natural products into contact with DNA. We will test the first hypothesis by obtaining energetic profiles of the possible pathways for cyclization and hydrogen abstraction of the natural products. Then, we will determine which portions of the molecule are essential for the lower reaction pathways found in step one. The second hypothesis will be tested by developing parameters for the enediynes natural products suitable for use with AMBER8. 8.Then, we will run Molecular Dynamics simulations that will show the effect of the enediynes sugars on the DNA recognition process.