Design and Synthesis of Inhibitors for Orotidine-5'-Monophosphate Decarboxylase

乳清苷-5-单磷酸脱羧酶抑制剂的设计与合成

基本信息

批准号：
8638976
负责人：
Weiming Wu
金额：
$ 23.1万
依托单位：
SAN FRANCISCO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8638976
关键词：
Accounting Active Sites Affect Affinity Amino Acids Anabolism Antimalarials Antiviral Agents Applications Grants Binding Carboxy-Lyases Catalysis Charge DNA Decarboxylation Development Electrons Enzymatic Biochemistry Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Goals Grant Journals Knowledge Lead Nucleotide Biosynthesis Nucleotides Organic Chemistry Organism Orotidine-5&apos -Phosphate Decarboxylase Pathway interactions Physiological Positioning Attribute Publications Purines Pyridoxal Phosphate Pyrimidine RNA Reaction Relative (related person)Research Structure Testing Therapeutic Thiamine Pyrophosphate Uridine Monophosphate Work Xanthines analog antitumor drug base carboxylate cofactor decarboxylase inhibitor design dipole moment drug candidate enzyme mechanism enzyme structure inhibitor/antagonist insight interest novel nucleotide analog nucleotide metabolism orotidylic acid purine research study xanthosine

Accounting Active Sites Affect Affinity Amino Acids Anabolism Antimalarials Antiviral Agents Applications Grants Binding Carboxy-Lyases Catalysis Charge DNA Decarboxylation Development Electrons Enzymatic Biochemistry Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Goals Grant Journals Knowledge Lead Nucleotide Biosynthesis Nucleotides Organic Chemistry Organism Orotidine-5&apos -Phosphate Decarboxylase Pathway interactions Physiological Positioning Attribute Publications Purines Pyridoxal Phosphate Pyrimidine RNA Reaction Relative (related person)Research Structure Testing Therapeutic Thiamine Pyrophosphate Uridine Monophosphate Work Xanthines analog antitumor drug base carboxylate cofactor decarboxylase inhibitor design dipole moment drug candidate enzyme mechanism enzyme structure inhibitor/antagonist insight interest novel nucleotide analog nucleotide metabolism orotidylic acid purine research study xanthosine

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项目摘要

DESCRIPTION (provided by applicant): Orotidine 5'-monophosphate decarboxylase (ODCase) is a key enzyme in the de novo pyrimidine biosynthetic pathway. This pathway is essential for the biosynthesis of building blocks for both DNA and RNA, and thus inhibitors of ODCase could have significant therapeutic value. Despite recent significant advances, it is not understood what factors are important in binding to and catalysis by ODCase. The lack of such knowledge is a critical deficit because understanding these factors is essential to the design of potent inhibitors for this enzyme. Our long-range goal is to understand the catalytic mechanism of ODCase and to design potent inhibitors of ODCase based on the mechanism. The objective of this application, which is a step in pursuit of that goal, is the identification of structural components of the substrate and its analogs that are important for binding and catalysis. The central hypothesis of the application is that the active site is structured to preferentially bind nucleotides with large matched dipole moment (as a result of an overall negative charge around the heterocyclic ring). The rationale for the proposed research is that, once the structural features determining tight binding between the enzyme and nucleotides are identified, novel potent inhibitors can be designed, which could serve as lead compounds in the design of drug candidates. The hypothesis will be tested by pursuing the following two specific aims: 1) Determine how the negative charge on the nucleotide base and the relative positions of the pyrimidine moiety to the phosphoribose moiety affect the binding of substrate analogues; and 2) Determine structural requirement for substrate binding and to eventually identify amino acid residues interacting with the substrate carboxylate group.

描述（由申请人提供）：Orotidine 5'-单磷酸脱羧酶（ODCASE）是从头嘧啶生物合成途径的关键酶。该途径对于DNA和RNA的构建基块的生物合成至关重要，因此ODCase的抑制剂可能具有显着的治疗价值。尽管最近取得了重大进展，但尚不了解哪些因素在与ODCASE结合和催化的结合和催化中很重要。缺乏这种知识是一个严重的赤字，因为理解这些因素对于该酶的有效抑制剂的设计至关重要。我们的远距离目标是了解ODCase的催化机制，并根据该机制设计有效的ODCase抑制剂。该应用的目的是追求该目标的一步，是鉴定基材的结构成分及其对结合和催化很重要的类似物。该应用的中心假设是，活性位点结构为优先结合具有较大偶极矩的核苷酸（由于杂环环周围的总体负电荷）。拟议研究的理由是，一旦确定酶和核苷酸之间紧密结合的结构特征，就可以设计出新的有效抑制剂，这可以用作候选药物设计的铅化合物。该假设将通过追求以下两个具体目的来检验：1）确定核苷酸基碱基上的负电荷如何以及嘧啶部分与磷酸咖啡部分的相对位置如何影响底物类似物的结合； 2）确定底物结合的结构需求，并最终鉴定与底物羧酸盐组相互作用的氨基酸残基。