Computer-Guided Molecular Design

该奖项由2009年美国复苏和再投资法案(公法111-5)资助。国家科学基金会化学部的有机和高分子化学项目支持纽约州立大学石溪分校的Dale G.Drueckhammer教授，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CAVERATE的应用，该程序是一个独特的程序，允许在电子数据库中搜索具有与一组定义的矢量匹配的键的化合物。在这一方法学的继续发展中，一个重点将是将荧光基团加入到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。该方法的新应用将是设计新的多肽/蛋白质受体。这些受体将基于支架结构上一对砷功能的展示，该支架结构使用CAVERATE设计，使它们将与α-螺旋多肽或蛋白质中一对特定位置的半胱氨酸残基的硫醇形成可逆的共价键。该项目的另一个主要应用将是开发一种新型的核酸模拟物，旨在展示与特定RNA序列结合的高亲和力和选择性。该设计结合了一系列的嘌呤和嘧啶碱基，每个碱基都连接到呋喃部分，各个单元通过呋喃环通过连接结构连接，连接结构使用警告。这一设计将展示一个基本的新概念，即如何使用基于警告的设计在寡聚结构上显示规则重复的功能阵列，这一想法预计将有更广泛的应用。最终提出的应用是探索一种二聚铁-配体络合物，旨在以分子氧为唯一氧化剂进行受控氧化反应。这项研究将用于设计一种连接这对配体的结构，以促进分子氧分裂成一对活性铁-氧物种。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，该项目还将为本科生和BS/MS联合项目的学生提供培训。所开发的设计方法将普遍适用于化学及相关领域中的各种问题和应用，并可能成为分子设计的一种广泛使用的方法。这项工作与传感器开发特别相关，传感器开发可能在医学、环境、国防和国土安全等领域有应用。德鲁克哈默教授继续开发的改进的虚拟分子数据库可能会使其他研究人员注意到它们的广泛适用性，并将根据要求随时向他们提供这些数据库。

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.