The Realisation of Fragment-Oriented Synthesis

面向片段合成的实现

• 批准号: EP/P016618/1
• 负责人: Stephen Marsden
• 金额: $ 73.2万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FP016618%2F1
• 关键词: Realisation; Fragment; Oriented; Synthesis

Despite the rise of biological therapies, the discovery of new and improved medicinal agents to treat disease is still dominated by small molecules. The challenges in discovering a new molecular medicine are significant indeed - typically taking about 12 years from laboratory to patient, and costing of the order of $2 bn for each new drug. As a result, the pharmaceutical industry is continually looking for new approaches to improve the efficiency and productivity of the drug discovery process.The binding of a drug to its target protein can be likened to the fitting of a key into a lock, and the design of molecular 'keys' that have the appropriate arrangements of teeth and grooves to complement the 'lock' of the protein binding site is a major challenge - particularly when one considers that the protein binding sites (and hence the molecules that need to interact with them) are generally highly complex and three-dimensional in shape. One approach to this problem, that has become increasing important over the last 15-20 years, is fragment-based drug discovery (FBDD). Here, the drug discovery process begins with fragments: very small molecules that are broadly analogous to an individual groove or tooth motif of a key. Fragments are then grown iteratively (to add more grooves and/or teeth) until promising larger and tighter-binding molecules are obtained. Although a relatively new approach, this method has already resulted in medicines that are being used clinically, for example against cancer.Despite the remarkable rise of FBDD, significant chemical challenges for the field have been identified by industry. For example, limitations in the synthetic chemistry toolkit mean that growth of fragments is much easier in some directions that others. We will therefore expand this toolkit to enable efficient the growth of fragments in many different directions. Crucially, we will demonstrate that our fragment-oriented synthesis (FOS) toolkit can drive the discovery of ligands for pharmaceutically-relevant proteins. To ensure alignment with future discovery needs, we will collaborate with a pharmaceutical company that specialises in FBDD. We will ensure that our FOS toolkit becomes embedded in different types of drug discovery organisations to maximise the impact of the work.

尽管生物疗法的兴起，但用于治疗疾病的新的和改进的药剂的发现仍然由小分子主导。发现一种新的分子药物的挑战确实是巨大的--从实验室到患者通常需要大约12年的时间，每种新药的成本大约为20亿美元。因此，制药行业不断寻找新的方法来提高药物发现过程的效率和生产力。药物与其靶蛋白的结合可以比作将钥匙插入锁中，而设计具有适当排列的齿和槽以补充蛋白质结合位点的“锁”的分子“钥匙”是一个主要挑战-特别是当考虑到蛋白质结合位点（以及因此需要与它们相互作用的分子）通常是高度复杂的和三维形状时。在过去的15-20年里，这个问题的一种方法变得越来越重要，这就是基于片段的药物发现（FBDD）。在这里，药物发现过程始于碎片：非常小的分子，大致类似于钥匙的单个凹槽或齿纹。然后片段迭代生长（以添加更多的凹槽和/或齿），直到获得有希望的更大和更紧密结合的分子。虽然是一种相对较新的方法，但这种方法已经导致药物被用于临床，例如抗癌。尽管FBDD的显着上升，但行业已经确定了该领域的重大化学挑战。例如，合成化学工具箱的局限性意味着片段的生长在某些方向上比其他方向容易得多。因此，我们将扩展这个工具包，使碎片在许多不同的方向上有效地增长。至关重要的是，我们将证明我们的片段导向合成（FOS）工具包可以驱动药物相关蛋白质配体的发现。为了确保与未来的发现需求保持一致，我们将与一家专门从事FBDD的制药公司合作。我们将确保我们的FOS工具包嵌入到不同类型的药物发现组织中，以最大限度地发挥工作的影响。