CHARACTERIZATION OF TRANSITION STATES IN BIOORGANIC REACTIONS

提出了几个项目，以进一步提高研究人员的能力 确定生物有机反应的过渡态结构。这个 这项研究的生物医学意义在于它在 理解Rational中努力的基本原则 药物设计。许多疾病过程都是一种酶的结果。 功能失控。这些酶是用药物控制的， 作为酶的抑制剂。抗病原剂也经常 特定病原体的关键代谢酶的特定抑制剂。 理解过渡态结构是合理设计的核心 作为酶抑制剂的药物。《公约》的具体目标 项目包括： 1.确定氢键在决定 酶模型反应中碱基的反应性。溶剂同位素 同位素效应、底物同位素效应和同位素效应 将被用来研究过渡过程中碱基脱溶的程度 从碳酸进行质子转移的状态。在多大程度上 溶剂围绕碱基的运动与质子转移事件相耦合 也将被确定。 2.发展计算碳同位素分馏系数的方法 强氢键在酶催化中被认为是重要的。 最近，几位研究人员提出了关于人类起源的新理论。 酶催化力。短而强的氢的稳定作用 键被认为是酶使用的机制的中心特征 以降低化学反应的屏障高度。目前的建议 是一项开发模型计算方法的计划，该方法可用于 检验和进一步提炼酶催化理论。 3.利用碳同位素效应确定过渡态结构 在酶促脱羧基反应中。一种基于激光的高精度激光加工新技术 将开发和测试同位素比率的精确测量 用于研究酶催化反应的机理。

Several projects are proposed to further the ability of researchers to determine the transition-state structure of bioorganic reactions. The biomedical significance of the research is the improvements it offers in understanding the fundamental principles underlying efforts in rational drug design. Many disease processes are the result of an enzyme functioning out of control. The enzymes are controlled using drugs that act as inhibitors of the enzyme. Antipathogenic agents are also often specific inhibitors of key metabolic enzymes of a particular pathogen. Understanding transition-state structure is central to the rational design of medicines that act as enzyme inhibitors. The specific aims of the project are: 1. To define the role that hydrogen bonds play in determining the reactivity of bases in model reactions for enzymes. Solvent isotope effects, substrate isotope effects, and isotope effects on isotope effect will be used to study the extent of base desolvation in the transition state for a proton transfer from a carbon acid. The degree to which solvent motions around the base are coupled to the proton transfer event will also be determined. 2. To develop methods for calculating isotopic fractionation factors of strong hydrogen bonds thought to be important in enzymic catalysis. Several researchers have proposed recently new theories about he origins of enzymic catalytic power. The stabilizing effects of short, strong hydrogen bonds are thought to be central features of the mechanisms used by enzymes to reduce the barrier heights for chemical reactions. The present proposal is a plan to develop methods for model calculations which can be used to test and further refine theories of enzymic catalysis. 3. To use carbon isotope effects to determine transition state structures in enzymic decarboxylations. A new laser-based technique for high- precision measurements of isotope ratios will be developed and tested for use in studying the mechanisms of reactions catalyzed by enzymes.