EPSRC Centre for Doctoral Training in Automated Chemical Synthesis Enabled by Digital Molecular Technologies

高效合成仍然是药物发现过程中的瓶颈。获取新的生物活性分子来治疗疾病仍然是制药行业的一个主要瓶颈，每年花费许多生命和数百万英镑的医疗保健投资和生产力损失。2016年，制药行业在研发（R&D）上的年度支出估计超过1570亿美元。在全国范围内，制药行业占英国2016年165亿英镑研发支出的近一半，其中7亿英镑投资于临床前小分子合成，995家制药相关企业（大型制药公司、中小企业、生物技术和cro）在英国研发部门雇用了约23,000名员工。该部门及其产出对国家生产力的影响是无可争辩的，值得投资于新的方法和技术，以推动进一步的创新和发展。随着对精准医学和对疾病的遗传理解的日益关注，有效和高选择性分子靶点的数量将急剧增加；确定基因信息靶点可以使临床开发的成功率提高一倍（Nat. Gen. 2015,47, 856）。然而，尽管化学研究取得了巨大的进步，但由于成本限制和紧迫的商业时间表，我们仍然无法准备所有潜在的药物开发兴趣分子。例如，默克引用了55%的时间，基准催化反应不能产生期望的产物；该统计数据将在整个制药行业具有代表性，并将适用于许多可比工艺。如果我们尝试的基础反应中有一半以上失败，那么我们将面临相当大的挑战，这将需要在合成方面进行彻底和创新的一步改变。这种合成逻辑的范式转变需要新一代高技能的学术和行业研究人员来推动，他们可以将创新的化学合成和技术进步与当前数据驱动科学、机器学习方法和人工智能的革命结合起来。拥有这样一套技能的合成化学家在世界上任何地方都不存在，然而世界范围内对具有跨这些学科工作能力的个人的需求正在迅速增长，并且将由这个提议的CDT独特地解决。通过培训下一代研究人员使用数字分子技术解决合成化学中的问题，我们将创造一支独特的、高技能的研究队伍，他们将应对这些挑战，并将英国的学术和工业部门置于分子建筑科学的前沿。下一代化学合成的目标应该是制备任何感兴趣的分子，而不受我们迄今所依赖的合成方法和制备技术的限制。学术界和工业界都缺乏具备这些技能和接触新技术的合成化学家，他们需要超越当前的限制进行创新，并提供应对未来生物医学挑战所需的范式转变。为了应对这些挑战，剑桥大学提议建立一个由数字分子技术支持的自动化化学合成博士培训中心，以招募、培训和发展下一代研究人员，以创新和引领未来的化学合成。

Efficient synthesis remains a bottleneck in the drug discovery process. Access to novel biologically active molecules to treat diseases continues to be a major bottleneck in the pharmaceutical industry, costing many lives and many £millions per year in healthcare investment and loss in productivity. In 2016, the Pharmaceutical Industry's estimated annual global spend on research and development (R&D) was over $157 billion. At a national level, the pharmaceutical sector accounted for almost half of the UK's 2016 £16.5bn R&D expenditure, with £700 million invested in pre-clinical small molecule synthesis, and 995 pharmaceutical related enterprises (big pharma, SMEs, biotech & CROs) employing around 23,000 personnel in UK R&D. The impact of this sector and its output on the nation's productivity is indisputable and worthy of investment in new approaches and technologies to fuel further innovation and development.With an increasing focus on precision medicine and genetic understanding of disease there will be to a dramatic increase in the number of potent and highly selective molecular targets; identifying genetically informed targets could double success rates in clinical development (Nat. Gen. 2015, 47, 856). However, despite tremendous advances in chemical research, we still cannot prepare all the molecules of potential interest for drug development due to cost constraints and tight commercial timelines. By way of example, Merck quote that 55% of the time, a benchmarked catalytic reaction fails to deliver the desired product; this statistic will be representative across pharma and will apply to many comparable processes. If more than half of the cornerstone reactions we attempt fail, then we face considerable challenges that will demand a radical and innovative a step change in synthesis. Such a paradigm shift in synthesis logic will need to be driven by a new generation of highly skilled academic and industry researchers who can combine innovative chemical synthesis and technological advances with fluency in the current revolution in data-driven science, machine learning methods and artificial intelligence. Synthetic chemists with such a set of skills do not exist anywhere in the world, yet the worldwide demand for individuals with the ability to work across these disciplines is increasing rapidly, and will be uniquely addressed by this proposed CDT. By training the next generation of researchers to tackle problems in synthetic chemistry using digital molecular technologies, we will create a unique, highly skilled research workforce that will address these challenges and place UK academic and industrial sectors at the frontier of molecule building science. The aspiration of next-generation chemical synthesis should be to prepare any molecule of interest without being limited by the synthetic methodologies and preparation technologies we have relied on to date. Synthetic chemists with the necessary set of such skills and exposure to the new technologies, required to innovate beyond the current limitations and deliver the paradigm shift needed to meet future biomedical challenges, are lacking in both academia and industry.To meet these challenges, the University of Cambridge proposes to establish a Centre of Doctoral Training in Automated Chemical Synthesis Enabled by Digital Molecular Technologies to recruit, train and develop the next generation of researchers to innovate and lead chemical synthesis of the future.