Autonomous Discovery of Functional Small Molecules

小分子药物继续主导人类治疗疾病的能力。然而，制药行业在多个方面面临前所未有的挑战。该行业受到药物发现失败率（超过95%）的严重影响，目前的成本/推出约为18亿英镑。大约45%的成本在药物发现的早期下降，因为相对较少的活动进行到治疗产品的推出。为了应对该行业提高生产率的巨大挑战，迫切需要更大的创新。药物与其靶蛋白的结合大致类似于将钥匙插入锁中。一个主要的挑战是优化药物的结构，使其与靶蛋白完美互补。目前的做法依赖于合成许多分子，然后单独纯化，然后测试改善的生物功能。需要许多循环来发现具有最佳性质的分子，并且在活性差的化合物的合成和纯化中花费了许多努力。因此，优化是漫长、费力和资源密集型的。我的奖学金将使我能够开发一个自主平台，用于发现功能分子。该方法将利用化学，使许多不同分子的功能能够并行探索，以确定对生物活性重要的特征。整个发现方法将自动化，一轮产品的功能直接通知下一轮反应的设计。与大多数药物化学方法不同，只有当检测到令人兴奋的改善的生物活性时，产品才会被纯化和鉴定。因此，这种方法非常有效，因为资源只集中在那些产生功能改善的分子的反应上。由此产生的分子可以作为药物发现计划的高度创新的起点。我将展示我的新方法可以支持功能分子发现的互补策略。至关重要的是，我将证明它可以发现配体-“钥匙”-一系列越来越具有挑战性的，医学相关的靶蛋白。这项活动将确保我的新方法得到从事小分子发现的科学家的充分赞赏。为了确保与未来的发现需求保持一致，我将与两家主要的制药公司合作，并与广泛的药物发现组织广泛接触。在项目的最后，我将定义一种机制，以确保我的方法对基于发现的行业中的最终用户是可用的。因此，我将确保我的新平台能够促进未来候选药物的发现。

Small molecule drugs continue to dominate Man's ability to treat disease. However, the pharmaceutical industry faces unprecedented challenges on multiple fronts. The sector is dogged by a crippling failure rate in drug discovery (over 95%), and a current cost/launch of ~£1.8bn. Around 45% of the costs fall early in drug discovery because relatively few campaigns proceed to the launch of a therapeutic product. Greater innovation is urgently required to address the sector's grand challenge of improving productivity.The binding of a drug to its target protein is broadly analogous to the fitting of a key into a lock. A major challenge is to optimise the structure of the drug so that it complements its target protein perfectly. Current practices rely on the synthesis of many molecules that are then individually purified and then tested for improved biological function. Many cycles are required to discover a molecule with optimal properties, and much effort is expended in the synthesis and purification of poorly active compounds. Optimisation is thus lengthy, laborious and resource-intensive. My fellowship will enable me to develop an autonomous platform for the discovery of functional molecules. The approach will exploit chemistry that enables the function of many different molecules to be explored in parallel, in order to determine features are important for biological activity. The whole discovery approach will be automated, with the functions of the products in one round directly informing the design of reactions in the next round. Unlike most medicinal chemistry approaches, products will only be purified and identified when exciting improved biological activity is detected. The approach is thus remarkably efficient because resources are focused overtly on only those reactions that yield molecules with improved function. The resulting molecules may serve as highly innovative starting points for drug discovery programmes. I will show that my novel approach can support complementary strategies for functional molecule discovery. Crucially, I will demonstrate that it can enable the discovery of ligands - "keys" - for a range of increasingly challenging, medicinally-relevant, target protein. This activity will ensure that my novel approach is fully appreciated by scientists engaged in small molecule discovery. To ensure alignment with future discovery needs, I will collaborate with two major pharmaceutical companies and engage extensively with a wide range of drug discovery organisations. At the end of the project, I will define a mechanism that will ensure that my approach is accessible to end-users in discovery-based industries. Thus, I will ensure that my novel platform can facilitate the discovery of future drug candidates.