IMPDH: Structural Determinants of Specificity

IMPDH：特异性的结构决定因素

• 批准号: 6424608
• 负责人: BARRY M GOLDSTEIN
• 金额: $ 24.07万
• 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 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6424608
• 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.

描述(申请人提供)：肌苷单磷酸脱氢酶 (IMPDH，E.C.I.1.1.205)是一种酶，其功能与 控制细胞的增殖和分化。它早就被人们认识到了 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射线结晶学来提供 与化学治疗活性二核苷酸类似物结合的第一类结构 人类IMPDH。这些信息将与生化和 生物数据。目标是确定特定的结构特征 绑定所需的。长期目标是设计具有以下特点的新代理 活动能力和临床疗效均有改善。 IMPDH催化鸟嘌呤从头合成的关键步骤 核苷酸。抑制IMPDH会损害G蛋白的作用能力 作为细胞内信号的换能器。抑制会导致减少 核酸合成、癌基因表达，最终是细胞 增殖分化。已经鉴定出两种IMPDH亚型， 标记为I型和II型。I型在正常细胞中结构性表达。 II型在肿瘤中的表达和活性显著上调 以及其他快速分裂的细胞。这种异构体一直是 药物设计。 噻唑呋喃是一种通过抑制IMPDH发挥作用的抗肿瘤药物。同相 II临床试验，噻唑呋喃取得了血液学完全缓解 终末期急性白血病患者。噻唑呋喃是一种前药。在体内，它 被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TAD(噻唑-4-甲酰胺腺嘌呤 二核苷酸)是IMPDH的主要抑制物。TAD的硒类似物， 称为SAD，以同样的效果绑定IMPDH。 首席调查员已经获得了一个复合体的结构， 人类II型IMPDH亚型和二核苷酸抑制剂SAD。这些数据 证明结合的抑制物的位置和构象，并表明 可在化合物开发中利用的特定相互作用 具有更高的亲和力和特异性。首席调查员将检查 I型和II型IMPDH结合的药物设计用于1)检验假设 分子内限制增强了结合和2)增强了特异性 II型异构体和克服与耐药性相关的临床问题 和快速新陈代谢。