Computer-Guided Molecular Design

计算机引导分子设计

• 批准号: 0848334
• 负责人: Dale Drueckhammer
• 金额: $ 38.04万
• 依托单位: SUNY at Stony Brook
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0848334&HistoricalAwards=false
• 关键词: Computer; Guided; Molecular; Design

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).The Organic and Macromolecular Chemistry Program in the Chemistry Division at the National Science Foundation supports Professor Dale G. Drueckhammer at the SUNY Stony Brook whose research will further develop and demonstrate a general computer-based method for molecular design. The project is based on applications of the computer program CAVEAT, which is a unique program that allows the search of electronic databases for compounds having bonds that match a set of defined vectors. In continued development of this methodology, one focus will be on the incorporation of fluorescent groups into a glucose receptor designed using this approach to achieve fluorescence-based sensing. A new application of the method will be the design of novel peptide/protein receptors. These receptors will be based on the display of a pair of arsenic functionalities on a scaffold structure designed using CAVEAT such that they will form reversible covalent bonds with the thiol groups of a pair of specifically positioned cysteine residues in an alpha-helical peptide or protein. Another major application of this project will be the development of a novel nucleic acid mimic, designed to exhibit high affinity and selectivity in binding to a specific sequence of RNA. The design incorporates a sequence of purine and pyrimidine bases each attached to a furan moiety, with individual units connected via the furan rings by a linker structure identified using CAVEAT. This design will demonstrate a fundamental new concept into how to use CAVEAT-based design to display a regular repeating array of functionality on an oligomeric structure, an idea that is expected to have broader applications. The final proposed application is to explore a dimeric iron-ligand complex designed to perform controlled oxidation reactions with molecular oxygen as the sole oxidant. CAVEAT will be used to design a structure to link the pair of ligands to facilitate the splitting of molecular oxygen into a pair of reactive iron-oxygen species.The broader impacts of this research will be to provide training to students in computer-based design methods and synthetic chemistry. In addition to PhD students, the project will provide training to undergraduates, and students in a combined BS/MS program. The design methods developed will be generally applicable to a wide variety of problems and applications in chemistry and related fields and may become a widely used approach to molecular design. The work has special relevance to sensor development, which may have applications in fields including medicine, the environment, defense, and homeland security. The improved virtual molecular databases that Professor Drueckhammer continues to develop, may bring their broad applicability to the attention of other investigators to whom they will be made readily available upon request.

该奖项根据 2009 年《美国复苏和再投资法案》（公法 111-5）提供资助。美国国家科学基金会化学部的有机和高分子化学项目为纽约州立大学石溪分校的 Dale G. Drueckhammer 教授提供支持，他的研究将进一步开发和展示基于计算机的通用分子设计方法。该项目基于计算机程序 CAVEAT 的应用，这是一个独特的程序，允许在电子数据库中搜索具有与一组定义的向量匹配的键的化合物。在这种方法的持续开发中，一个重点将是将荧光基团纳入使用这种方法设计的葡萄糖受体中，以实现基于荧光的传感。该方法的一个新应用将是新型肽/蛋白质受体的设计。这些受体将基于使用 CAVEAT 设计的支架结构上一对砷功能的展示，这样它们将与 α 螺旋肽或蛋白质中一对特定定位的半胱氨酸残基的硫醇基团形成可逆共价键。该项目的另一个主要应用是开发一种新型核酸模拟物，旨在与特定的 RNA 序列结合时表现出高亲和力和选择性。该设计包含一系列嘌呤和嘧啶碱基，每个碱基连接到一个呋喃部分，各个单元通过呋喃环通过使用 CAVEAT 识别的连接体结构连接。该设计将展示一个基本的新概念，即如何使用基于 CAVEAT 的设计在寡聚结构上显示规则的重复功能阵列，这一想法有望拥有更广泛的应用。最终提出的应用是探索一种二聚铁配体复合物，旨在以分子氧作为唯一氧化剂进行受控氧化反应。 CAVEAT 将用于设计一种连接一对配体的结构，以促进分子氧分裂成一对活性铁氧物质。这项研究的更广泛影响将是为学生提供基于计算机的设计方法和合成化学的培训。除了博士生外，该项目还将为本科生以及学士/硕士联合课程的学生提供培训。所开发的设计方法将普遍适用于化学及相关领域的各种问题和应用，并可能成为广泛使用的分子设计方法。这项工作与传感器开发特别相关，可能在医学、环境、国防和国土安全等领域得到应用。 Drueckhammer 教授继续开发的改进的虚拟分子数据库可能会使其广泛的适用性引起其他研究人员的注意，我们将根据要求随时向他们提供这些数据库。