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Covalent and Transition State Inhibitor Design

共价和过渡态抑制剂设计

基本信息

批准号：
1808449
负责人：
Andrew Murkin
金额：
$ 46.8万
依托单位：
SUNY at Buffalo
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1808449&HistoricalAwards=false
关键词：
Covalent Transition State Inhibitor Design

项目摘要

This award funds Professor Andrew Murkin of the University at Buffalo, The State University of New York, to develop a series of compounds that may serve as specific inhibitors of an enzyme critical to metabolism in plants and bacteria, known as isocitrate lyase (ICL). One of the obstacles to inhibitor design is ensuring selective binding to ICL over other potential targets. Meeting this goal usually requires a special interaction or group of interactions between the inhibitor and the enzyme. One strategy for accomplishing this is to introduce a part of an inhibitor that only sticks to the target if it is in just the right place for an interaction. A second strategy is to have the inhibitor resemble what is happening during the catalyzed conversion. This tricks the enzyme into binding to the inhibitor tightly and with great specificity. The current research aims to develop compounds that inhibit ICL by one of these two strategies, which may prove to be a general means for inhibiting numerous enzymes. Educational development is provided to undergraduate and graduate students, and local area teachers will be trained to perform hands-on lessons that introduce enzymes to K-12 students.This project exploits two properties of aliphatic nitro compounds that may lead to potent enzyme inhibition. The first of these is previously unknown and therefore investigated in detail. Specifically, the carbon adjacent to the nitro group can act as an electrophile for covalent reaction with a neighboring cysteine residue under certain conditions when bound to an enzyme. Kinetic, mass spectral, and X-ray crystallographic experiments are proposed to elucidate the mechanism by which this reaction occurs between a simple nitro compound and ICL. In an attempt to improve selectivity, more elaborate nitro compounds will be prepared and tested. The second property of nitro compounds that will be utilized here is the resemblance of their conjugate bases, called nitronates, to the aci enolate form of their carboxylic acid equivalents. Through the use of kinetic isotope effects and computational modeling, the transition state of ICL will be determined. Nitronate analogues of the transition state will be prepared, with the goal of obtaining strong binding with ICL.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该奖项资助纽约州立大学布法罗分校的Andrew Murkin教授开发一系列化合物，这些化合物可能作为植物和细菌代谢关键酶的特异性抑制剂，称为异柠檬酸裂解酶（ICL）。抑制剂设计的障碍之一是确保选择性结合ICL而不是其他潜在靶点。实现这一目标通常需要抑制剂和酶之间的特殊相互作用或一组相互作用。实现这一目标的一个策略是引入抑制剂的一部分，只有当它恰好处于相互作用的正确位置时，它才会粘附在目标上。第二种策略是使抑制剂类似于催化转化过程中发生的情况。这诱使酶与抑制剂紧密结合，并具有很强的特异性。目前的研究旨在通过这两种策略中的一种来开发抑制ICL的化合物，这可能被证明是抑制许多酶的一般手段。为本科生和研究生提供教育发展，当地教师将接受培训，向K-12学生介绍酶的实践课程。该项目利用脂肪族硝基化合物的两个特性，可能导致有效的酶抑制。其中第一个以前是未知的，因此进行了详细的研究。具体来说，当与酶结合时，与硝基相邻的碳在一定条件下可以作为亲电试剂与相邻的半胱氨酸残基进行共价反应。提出了动力学、质谱和x射线晶体学实验来阐明简单硝基化合物与ICL之间发生反应的机理。为了提高选择性，将制备和测试更精细的硝基化合物。这里要用到的硝基化合物的第二个性质是它们的共轭碱，称为硝基酸盐，与它们的羧酸等价物的酸烯醇酯形式的相似性。通过利用动力学同位素效应和计算模型，将确定ICL的过渡态。将制备过渡态的硝酸盐类似物，目的是与ICL强结合。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。