Understanding mechanism of action: Combined computational and structural biology studies to determine small molecule effects on protein dynamics and function

了解作用机制：结合计算和结构生物学研究来确定小分子对蛋白质动力学和功能的影响

• 批准号: 555689-2020
• 负责人: Trant, JohnJF
• 金额: $ 11万
• 依托单位: University of Windsor
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748432
• 关键词: Understanding; mechanism; action; Combined; computational

Cotinga Pharmaceuticals, a Canadian biopharma company, and the University of Windsor, professors John Trant, Yufeng Tong, and Lisa Porter will be collaborating on understanding the mechanisms of action for small molecules and certain proteins that are found in many cancers. When proteins become mutated, they cease to function properly and this can allow cells to grow uncontrollably causing disease. Often the mutation simply involves changing one of the thousands of amino acids that make up the protein for a different amino acid. This is often enough to cause the protein to adopt a different shape. This prevents it from doing its job in the cell. Cotinga has developed several drugs in clinical trials and needs to better understand how they interact with specific human proteins. The UWindsor team will be using a combination of computer simulations of the protein-molecule interactions and experimental measurements of these interactions. The team will also be using crystallography to get "pictures" of the molecules interacting with the proteins to make sure that they are the true targets of these molecules. This five year project will not only advance Cotinga's science, it will also help us better understand how molecules can help misfolded proteins regain their proper shape, why proteins fold the way they do, and why proteins interact with other proteins the way they do. This project consequently advances the economic interests of a Canadian company, assists in providing exceptional multidisciplinary training to the students and postdoctoral fellows working on it preparing them for employment in the chemical industry, and also improves humanity's understanding of the basic behaviour of these very important proteins.

加拿大生物制药公司Cotinga Pharmaceuticals和温莎大学教授John Trant、Yufeng Tong和丽莎Porter将合作了解在许多癌症中发现的小分子和某些蛋白质的作用机制。当蛋白质发生突变时，它们停止正常工作，这可能会使细胞无法控制地生长，从而导致疾病。通常，突变只是将组成蛋白质的数千种氨基酸中的一种改变为不同的氨基酸。这通常足以导致蛋白质采取不同的形状。这会阻止它在细胞中发挥作用。Cotinga已经在临床试验中开发了几种药物，需要更好地了解它们如何与特定的人类蛋白质相互作用。温莎大学的研究小组将使用蛋白质分子相互作用的计算机模拟和这些相互作用的实验测量相结合。该团队还将使用晶体学来获得与蛋白质相互作用的分子的“图片”，以确保它们是这些分子的真正目标。这个为期五年的项目不仅将推进Cotinga的科学，它还将帮助我们更好地了解分子如何帮助错误折叠的蛋白质恢复其正确的形状，为什么蛋白质折叠的方式，以及为什么蛋白质与其他蛋白质相互作用的方式。因此，该项目促进了一家加拿大公司的经济利益，有助于为从事该项目的学生和博士后研究员提供特殊的多学科培训，使他们为在化学工业就业做好准备，并提高了人类对这些非常重要的蛋白质的基本行为的理解。