STRUCTURE BASED DRUG DISCOVERY AND MECHANISTIC STUDIES OF PHOSPHORIBOSYLTRANSFER

基于结构的药物发现和磷酸核糖基转移机制研究

• 批准号: 7370343
• 负责人: PAMELA J FOCIA
• 金额: $ 0.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370343
• 关键词: STRUCTURE; BASED; DRUG; DISCOVERY; MECHANISTIC

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Many parasites lack de novo pathways for purine nucleotide biosynthesis and rely on salvage enzymes, such as the phosphoribosyltransferases, to acquire those needed for cellular metabolism, thus, the salvage pathways provide targets for anti-proliferative drug discovery. In addition, we are interested in studying the mechanism of hypoxanthine/guanine phosphoribosyltransferases, which catalyze a reversible, ordered, sequential, nucleophilic displacement reaction utilizing two divalent metal ions, which straddle the pyrophosphate leaving group, position the two substrates, and interact with an invariant aspartic acid residue. Closed active site forms of ternary complexes of the Trypanosomza cruzi and human enzymes are available that allow us to analyze structures captured right before the transition states of both the forward and reverse reactions, using a combination of natural substrates or products, and analogs. The closed active site ternary substrates complex of the HPRT from T. cruzi was targeted with DOCK, and several low micromolar inhibitors were further identified that were obtained directly from computational analyses. Many more compounds await characterization. Structures of complexes of the target with inhibitors will allow comparison of predicted to actual binding modes, and comparisons of parasite and human enzymes in complex with inhibitors might lend insight toward improving selectivity for the parasite enzymes.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。许多寄生虫缺乏嘌呤核苷酸生物合成的新生途径，依赖于磷酸核糖基转移酶等挽救酶来获得细胞代谢所需的酶，因此，挽救途径为抗增殖药物的发现提供了靶点。此外，我们有兴趣研究次黄嘌呤/鸟嘌呤磷酸核糖基转移酶的机制，它利用两个二价金属离子催化可逆的、有序的、顺序的亲核位移反应，这些离子横跨焦磷酸离去基，定位两个底物，并与不变的天冬氨酸残基相互作用。克氏锥虫和人类酶的三元配合物的封闭活性位点形式使我们能够利用天然底物或产物和类似物的组合来分析正反反应过渡状态之前捕获的结构。用DOCK靶向克氏t的封闭活性位点三元底物复合物，并通过计算分析进一步鉴定了几种低微摩尔抑制剂。更多的化合物有待鉴定。靶标与抑制剂配合物的结构将允许将预测的结合模式与实际的结合模式进行比较，并且寄生虫和人类酶在抑制剂配合物中的比较可能有助于提高寄生虫酶的选择性。