GOALI: D3SC: New Ligands and Understanding from Pharmaceutical Compound Libraries

目标：D3SC：新配体和对药物化合物库的理解

• 批准号: 1900366
• 负责人: Daniel Weix
• 金额: $ 48.5万
• 依托单位: University of Wisconsin-Madison
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1900366&HistoricalAwards=false
• 关键词: GOALI; D3SC; New; Ligands; Understanding

With this award, the Chemical Catalysis Program of the NSF Division of Chemistry is supporting the research of Professor Daniel Weix at the University of Wisconsin-Madison and Dr. Eric Hansen at Pfizer to explore new methods to find better catalysts for chemical reactions. Metal-catalyzed reactions are the key to improving the stewardship of the U.S.'s vast petrochemical resources and to discovering innovative, new medicines. Existing technology is based around scarce metals, such as palladium and rhodium, but recent developments with more earth-abundant metals, such as nickel, copper, and iron, show great promise. Unfortunately, there are currently few catalysts based around these more environmentally friendly and less expensive metals. This industrial-academic partnership is discovering new catalysts by mining an untapped resource, pharmaceutical compound libraries. Using these libraries of knowledge, the team is mining data to find new catalysts and to gather information on what properties make a good catalyst. Analysis of the collected data by researchers at Pfizer and UW-Madison, with the assistance of Professor Matthew Sigman at the University of Utah, guides the prediction of new catalysts and catalyst selection. The newly discovered catalysts are being made available to researchers through a partnership with Millipore-Sigma. This combination of experimental and computational training is preparing students to advance the use of data science in chemistry, an area that is rapidly growing in importance. This training includes students who are currently underrepresented in chemistry through partnerships with existing and new UW-Madison programs: the Chemistry Opportunities Program, Partners for Graduate School Experience in Chemistry, and the American Chemical Society BRIDGE to the Doctorate program.The UW-Madison team, led by Professor Weix, and the Pfizer team, led by Dr. Hansen, are systematically searching the very large Pfizer compound library for new ligands using an iterative experimental and computational approach inspired by fragment-based drug discovery. The goals of this collaboration are to discover new privileged ligands and to develop broadly applicable parameters and models. Diverse potential ligands sourced from the compound library are being screened against known reactions with different metal and ligand requirements to find new ligand core structures. These core structures are then being optimized using conventional methods. The data gathered is analyzed, in collaboration with Professor Sigman, to provide an understanding of which properties (if any) are universal for useful ligands and to predict improved ligands. The impacts of this this research program extend to the development of new ligands and versatile ligand precursors that are immediately made commercially available from Millipore-Sigma. The research may also result in better parameters and models that are useful for constructing a more diverse array of ligand types. The large data sets are helpful for developing new computational approaches made available through data repositories.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

有了这个奖项，NSF化学部的化学催化计划正在支持威斯康星大学麦迪逊分校的丹尼尔韦克斯教授和辉瑞公司的埃里克汉森博士的研究，以探索新的方法来寻找更好的化学反应催化剂。金属催化反应是改善美国能源管理的关键。丰富的石油化工资源和发现创新的新药。现有的技术是基于稀有金属，如钯和铑，但最近的发展与地球上更丰富的金属，如镍，铜和铁，显示出巨大的希望。不幸的是，目前几乎没有基于这些更环保和更便宜的金属的催化剂。这种工业-学术合作伙伴关系正在通过挖掘未开发的资源，即药物化合物库来发现新的催化剂。利用这些知识库，该团队正在挖掘数据，以寻找新的催化剂，并收集关于什么性质是好的催化剂的信息。辉瑞和威斯康星大学麦迪逊分校的研究人员在犹他州大学的Matthew Sigman教授的协助下对收集的数据进行分析，指导了新催化剂的预测和催化剂的选择。新发现的催化剂通过与Millipore-Sigma的合作提供给研究人员。这种实验和计算培训的结合使学生能够推进数据科学在化学中的应用，这是一个重要性迅速增长的领域。这项培训包括学生谁是目前在化学通过与现有的和新的威斯康星大学麦迪逊分校计划的合作伙伴关系代表不足：化学机会计划，化学研究生院经验的合作伙伴，和美国化学学会桥梁博士课程。威斯康星大学麦迪逊分校的团队，由Weix教授领导，辉瑞公司的团队，由博士领导。汉森，正在系统地搜索非常大的辉瑞化合物库的新配体使用迭代实验和计算方法的启发基于片段的药物发现。这项合作的目标是发现新的特权配体，并开发广泛适用的参数和模型。来自化合物库的各种潜在配体正在针对具有不同金属和配体要求的已知反应进行筛选，以找到新的配体核心结构。然后使用常规方法优化这些核心结构。与Sigman教授合作，对收集的数据进行分析，以了解哪些特性（如果有的话）对于有用的配体是通用的，并预测改进的配体。该研究计划的影响扩展到新配体和多功能配体前体的开发，这些配体和前体可立即从Millipore-Sigma商购获得。 该研究还可能导致更好的参数和模型，用于构建更多样化的配体类型阵列。 该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。