The Realisation of Fragment-Oriented Synthesis

尽管生物疗法的兴起，但治疗疾病的新的和改进的药物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12年左右的时间，每种新药的成本约为20亿美元。因此，制药业一直在寻找新的方法来提高药物发现过程的效率和生产率。药物与其目标蛋白质的结合可以比作将钥匙装进锁中，而设计具有适当排列的牙齿和沟槽以补充蛋白质结合部位的锁的分子“钥匙”是一个重大挑战--特别是当人们考虑到蛋白质结合部位(因此需要与其相互作用的分子)通常是高度复杂和三维形状的时候。解决这一问题的一种方法是基于片段的药物发现(FBDD)，在过去的15-20年里，这种方法变得越来越重要。在这里，药物发现过程从碎片开始：与钥匙的单个凹槽或牙齿图案广泛相似的非常小的分子。然后反复生长片段(以增加更多的凹槽和/或牙齿)，直到获得有希望的更大和更紧密结合的分子。尽管这是一种相对较新的方法，但这种方法已经导致了临床上使用的药物，例如对抗癌症的药物。尽管FBDD的显著上升，该领域的重大化学挑战已经被工业界发现。例如，合成化学工具包中的限制意味着片段在某些方向上的生长比在其他方向上容易得多。因此，我们将扩展此工具包，以实现在多个不同方向上高效地增长碎片。至关重要的是，我们将证明我们的面向片段的合成(FOS)工具包可以推动发现与药物相关的蛋白质的配体。为了确保与未来的发现需求保持一致，我们将与一家专门研究FBDD的制药公司合作。我们将确保我们的FOS工具包嵌入不同类型的药物发现组织，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.