MOLECULAR RECOGNITION IN BIOMIMETIC RECEPTORS

仿生受体中的分子识别

• 批准号: 3287557
• 负责人: ANDREW D HAMILTON
• 金额: $ 14.92万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1992-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3287557
• 关键词: Staphylococcus infection; alanine; barbiturates; beta lactam antibiotic; binding proteins; carbonyl group; carboxylation; catalyst; cell wall; chemical binding; chemical models; chemical stimulation; chemical structure function; chromatography; chymotrypsin; dihydroxyphenylalanine; drug design /synthesis /production; drug receptors; drug screening /evaluation; enzyme mechanism; hydrogen bond; nuclear magnetic resonance spectroscopy; nuclease; peptidoglycan; ristocetin; vancomycin

A new research program in the field of molecular recognition is proposed. We plan to design, synthesize and study two classes of molecular receptors which will recognize and selectively bind important biological molecules. The first class of receptors will be specific for the phenethylamines which have many important functions in biochemistry (e.g. dopamine, phenylalanine, tyrosine and L-DOPA). Component binding site units (e.g. for ammonium, phenyl, carboxylate and phenolic OH groups) will be prepared and put together in various combinations to form the receptors. The first target will be a ditopic receptor, containing ammonium and phenyl group binding sites, which recognizes the basic phenethylamine nucleus. Detailed structural, thermodynamic and kinetic studies will be performed on this and later systems to probe the relationship between receptor and substrate structure and the complexation process. Different tri-tetra- and pentatopic receptors will be prepared to recognize different derivatives of phenethylamine. In addition receptors containing chiral and/or reactive groups will be synthesized. These receptors should find important application in the transport of drugs, new chromatographic materials and biosensors. The second class of receptors will recognize terminal peptide carboxylate species and will be based on the important vancomycin family of antibiotics. We will prepare synthetic analogs of the right hand ring of vancomycin. This region contains a hydrophobic pocket and key groups that hydrogen bond to the carboxylate terminus of AcD-Ala-D-Ala in bacterial cell wall biosynthesis. Preliminary results and calculations suggest that an isolated ring should have the same conformation and chemical characteristics as the natural system. The first target will be the basic right hand ring structure. To this we will sequentially add an in N-terminal residue and carboxamide group to increase the number of H-bonds to the substrate and thus the recognition characteristics of the receptor. In later targets we will accurately model substituents in the antibiotics. For each system we will use a variety of physical techniques (NMR, uv-vis, etc.) to probe the structure and selectivity of complexation. We will also collaborate to screen these receptors for antimicrobial activity.

提出了分子识别领域的新研究计划。 我们计划设计，合成和研究两类的分子受体 它将识别并有选择地结合重要的生物分子。 第一类受体将是特定于苯乙胺的特定的 在生物化学中具有许多重要功能（例如多巴胺， 苯丙氨酸，酪氨酸和L-DOPA）。 组件结合位点单元（例如 对于铵，苯基，羧酸盐和酚类OH组）将制备 并组合各种组合以形成受体。 第一个 靶标将是含铵和苯基的斜视受体 结合位点，识别碱性苯乙胺核。 详细的 将在此上进行结构，热力学和动力学研究 以后的系统来探测受体与底物之间的关系 结构和络合过程。 不同的三环和 五角星受体将准备识别的不同衍生物 苯乙胺。 另外，含有手性和/或反应性的受体 组将合成。 这些受体应该发现重要 在药物的运输，新的色谱材料和 生物传感器。 第二类受体将识别末端肽羧酸盐 物种，将基于重要的万古霉素家族 抗生素。 我们将准备右手环的合成类似物 万古霉素。 该区域包含一个疏水口袋和关键基团 与细菌中ACD-ALA-D-ALA的羧酸酯末端氢键 细胞壁生物合成。 初步结果和计算表明 孤立的环应具有相同的构象和化学 特征作为自然系统。 第一个目标将是基本的 右手环结构。 为此，我们将依次添加 N末端残基和羧酰胺组增加了H键的数量 对底物，从而获得受体的识别特征。 在以后的目标中，我们将准确地模拟抗生素中的取代基。 对于每个系统，我们将使用各种物理技术（NMR，UV-VIS， 等）探测络合的结构和选择性。 我们也会 协作以筛选这些受体以进行抗菌活性。