IMPDH: Structural Determinants of Specificity

IMPDH：特异性的结构决定因素

• 批准号: 6898242
• 负责人: BARRY M GOLDSTEIN
• 金额: $ 26.46万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6898242
• 关键词: X ray crystallography; alcohol dehydrogenase; antineoplastics; drug design /synthesis /production; enzyme structure; guanine nucleotides; inosine monophosphate; isozymes; oxidoreductase inhibitor; protein binding; protein structure function

DESCRIPTION (provided by applicant): Inosine monophosphate dehydrogenase (IMPDH, E.C. I .1.1.205) is an enzyme whose function is closely linked with the control of cell proliferation and differentiation. It has long been recognized as an important target in the design of both anti-tumor, immunosuppressive and antiviral drugs. This project will use X-ray crystallography to provide the first structures of chemotherapeutically active dinucleotide analogues bound to human IMPDH. This information will be correlated with biochemical and biological data. The goal is the identification of specific structural features required for binding. The long-range goal is the design of new agents with improved activity and clinical efficacy. IMPDH catalyzes the committed step in the de novo synthesis of the guanine nucleotides. Inhibition of IMPDH compromises the ability of G proteins to act as transducers of intracellular signals. Inhibition results in reductions in nucleic acid synthesis, oncogene expression, and, ultimately, cell proliferation and differentiation. Two isoforms of IMPDH have been identified, labeled type I and type II. Type I is constitutively expressed in normal cells. Expression and activity of type II is dramatically up-regulated in neoplastic and other rapidly dividing cells. This isoform has been a primary target in drug design. Tiazofurin is an antitumor agent that functions by inhibiting IMPDH. In Phase II clinical trials, tiazofurin has produced complete hematologic remissions in patients with end-stage acute leukemias. Tiazofurin is a prodrug. In vivo, it is converted to an analogue of the cofactor nicotinamide adenine dinucleotide (NAD). This NAD analogue, called TAD (thiazole-4-carboxamide adenine dinucleotide) is the major inhibitor of IMPDH. The selenium analogue of TAD, called SAD, binds IMPDH with equal efficacy. The principal investigator has obtained a structure of a complex between the human type II isoform of IMPDH and the dinucleotide inhibitor SAD. These data demonstrate the location and conformation of the bound inhibitor, and indicate specific interactions which can be exploited in the development of compounds with improved affinity and specificity. The principal investigator will examine type I and II IMPDH binding by agents designed to 1) test the hypothesis that intramolecular constraints enhance binding and 2) enhance specificity for the type II isoform and overcome clinical problems associated with drug resistance and rapid metabolism.

性状（由申请方提供）：肌苷单磷酸脱氢酶 （IMPDH，E.C. I.1.1.205）是一种酶，其功能与 控制细胞增殖和分化。人们早就认识到 作为抗肿瘤、免疫抑制和抗肿瘤药物设计中的重要靶点， 抗病毒药物该项目将使用X射线晶体学来提供 结合到第一结构的化疗活性二核苷酸类似物 人IMPDH。这些信息将与生物化学和 生物数据。目标是识别特定的结构特征 需要绑定。长期目标是设计新的代理， 提高了活性和临床疗效。 IMPDH催化鸟嘌呤从头合成中的关键步骤 个核苷酸IMPDH的抑制损害G蛋白的作用能力 作为细胞内信号的转换器。抑制导致 核酸合成，癌基因表达，最终，细胞 增殖和分化。已经鉴定了IMPDH的两种同种型， 标记为I型和II型。I型在正常细胞中组成型表达。 肿瘤中II型的表达和活性显着上调 和其他快速分裂的细胞。这种异构体一直是一个主要目标， 药物设计 噻唑弗林是一种抗肿瘤药物，通过抑制IMPDH发挥作用。同相 II临床试验，硫唑福林已产生完全的血液学缓解， 晚期急性白血病患者。硫唑福林是一种前药。在体内，它 转化为辅因子烟酰胺腺嘌呤二核苷酸的类似物 （NAD）。这种NAD类似物，称为噻唑-4-甲酰胺腺嘌呤 二核苷酸）是IMPDH的主要抑制剂。硒的类似物， 称为SAD，以相同的效力结合IMPDH。 主要研究人员已经获得了一个复杂的结构之间的 IMPDH的人II型同种型和二核苷酸抑制剂SAD。这些数据 证明结合抑制剂的位置和构象，并指出 可用于化合物开发的特定相互作用 具有改进的亲和力和特异性。首席调查员会检查 通过设计用于1）检验以下假设的试剂结合I型和II型IMPDH， 分子内约束增强结合和2）增强对蛋白质的特异性。 II型同种型和克服与耐药性相关的临床问题 和快速的新陈代谢。