The Realisation of Fragment-Oriented Synthesis

尽管生物疗法的兴起，新的和改进的药物药物治疗疾病的发现仍然是由小分子主导的。发现一种新的分子药物的挑战确实很大——从实验室到患者通常需要12年左右的时间，每种新药的成本约为20亿美元。因此，制药行业正在不断寻找新的方法来提高药物发现过程的效率和生产力。药物与目标蛋白的结合可以被类比为把钥匙装进锁里，而分子“钥匙”的设计是一个主要的挑战，分子“钥匙”要有适当的齿和凹槽排列，以补充蛋白质结合位点的“锁”，特别是当人们考虑到蛋白质结合位点（因此需要与它们相互作用的分子）通常是高度复杂和三维的形状。解决这一问题的一种方法是基于片段的药物发现（FBDD），在过去15-20年中变得越来越重要。在这里，药物发现过程从片段开始：非常小的分子，大致类似于钥匙的单个凹槽或齿基序。然后片段迭代生长（增加更多凹槽和/或齿），直到获得更大、更紧密结合的分子。虽然这是一种相对较新的方法，但这种方法已经产生了用于临床的药物，例如抗癌药物。尽管FBDD的发展势头显著，但行业已经确定了该领域面临的重大化学挑战。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要比在其他方向上容易得多。因此，我们将扩展这个工具包，使片段能够在许多不同的方向上有效地生长。至关重要的是，我们将证明我们的片段导向合成（FOS）工具包可以推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。

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.