Probing the Structure, Mechanism and Inhibition of Indoleamine 2,3-Dioxygenase Using Structure- and Ligand-Based Studies

利用基于结构和配体的研究探讨吲哚胺 2,3-双加氧酶的结构、机制和抑制

• 批准号: nhmrc : 281505
• 负责人: A/Pr Joanne Jamie
• 金额: $ 21.31万
• 依托单位: Macquarie University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2004
• 资助国家: 澳大利亚
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/probing-structure-mechanism-based-studies/100090
• 关键词: Probing; Structure; Mechanism; Inhibition; Indoleamine

The human enzyme indoleamine 2,3-dioxygenase (IDO) is responsible for the initiation of a major enzymatic pathway, known as the kynurenine pathway. During certain immune and infectious diseases IDO becomes over-active and this leads to accumulation of neurotoxic kynurenine pathway compounds (metabolites). The elevated levels of these metabolites have been linked to severe mental deterioration associated with diseases such as AIDS (AIDS dementia complex), malaria and Alzheimer's disease. Several kynurenine pathway metabolites have also been linked to age-related nuclear cataract, which is the major cause of human blindness. This project employs a multidisciplinary approach that brings together a team of expert scientists from medicinal chemistry, protein crystallography, protein biochemistry and neurology. The overall aims of the project are to determine the structure of IDO using the recombinant human enzyme that we have cloned and expressed in an active form and to develop compounds that will regulate levels of the kynurenine pathway metabolites by selectively inhibiting the action of IDO. In addition, we will begin to assess the medicinal value of the best inhibitors. We have already synthesised several inhibitors of IDO, but wish to design more potent inhibitors. In order to do this, computer-aided molecular modelling and X-ray crystallography (which effectively provides a picture of the enzyme with the inhibitors attached) will be used to predict the best molecular features needed for inhibition. This will greatly aid the design of new inhibitor compounds, which will then be synthesised. The best inhibitors will also be examined to determine their general pharmacological value and specifically their ability to treat AIDS dementia complex and age-related nuclear cataract. These enzyme inhibitors also have the potential to treat other significant human diseases.

人类吲哚胺 2,3-双加氧酶 (IDO) 负责启动主要酶途径，称为犬尿氨酸途径。在某些免疫和传染病期间，IDO 变得过度活跃，这导致神经毒性犬尿氨酸途径化合物（代谢物）的积累。这些代谢物水平升高与艾滋病（艾滋病痴呆症）、疟疾和阿尔茨海默病等疾病相关的严重精神退化有关。几种犬尿氨酸途径代谢物也与年龄相关的核性白内障有关，这是人类失明的主要原因。该项目采用多学科方法，汇集了来自药物化学、蛋白质晶体学、蛋白质生物化学和神经病学的专家科学家团队。该项目的总体目标是使用我们克隆并以活性形式表达的重组人酶来确定 IDO 的结构，并开发通过选择性抑制 IDO 的作用来调节犬尿氨酸途径代谢物水平的化合物。此外，我们将开始评估最佳抑制剂的药用价值。我们已经合成了几种IDO抑制剂，但希望设计出更有效的抑制剂。为了做到这一点，计算机辅助分子建模和 X 射线晶体学（有效提供附着有抑制剂的酶的图像）将用于预测抑制所需的最佳分子特征。这将极大地有助于新抑制剂化合物的设计，然后进行合成。还将对最好的抑制剂进行检查，以确定其一般药理学价值，特别是其治疗艾滋病痴呆症和年龄相关性核性白内障的能力。这些酶抑制剂还具有治疗其他重大人类疾病的潜力。