CHARACTERIZATION OF TRANSITION STATES IN BIOORGANIC REACTIONS

提出了几个项目，以提高研究人员的能力， 确定生物有机反应的过渡态结构。 的 这项研究的生物医学意义在于它在以下方面提供了改进： 理解在合理的基础上努力的基本原则 药物设计 许多疾病的过程是一种酶 失去控制 这些酶被药物控制， 作为酶的抑制剂。 抗病原体药物也经常 特定病原体关键代谢酶的特异性抑制剂。 理解过渡态结构对于合理设计至关重要 作为酶抑制剂的药物。 的具体目标 项目有： 1. 为了确定氢键在决定分子结构中的作用， 酶的模型反应中的碱基反应性。 溶剂同位素 效应、底物同位素效应和同位素效应对同位素效应的影响 将被用来研究碱去溶剂化的程度在过渡 质子从碳酸转移的状态。 的程度 溶剂在基底周围的运动与质子转移事件相耦合 也将被确定。 2. 发展计算同位素分馏因子的方法， 被认为在酶催化中很重要的强氢键。 最近，一些研究人员提出了关于其起源的新理论。 酶催化能力 短而强的氢的稳定作用 键被认为是酶所使用的机制的中心特征 以降低化学反应的势垒高度。 现时的建议 是一项开发模型计算方法的计划， 测试和进一步完善酶催化理论。 3. 利用碳同位素效应确定过渡态结构 在酶的脱羧作用中。 一种新的基于激光的高分辨率成像技术， 将开发和测试同位素比的精确测量， 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.