Autonomous Phenotype-Directed Molecular Discovery

与开发新药相关的挑战确实非常重大。该过程通常包括选择与特定疾病相关的蛋白质靶标；识别和优化可以调节该目标的分子；以及涉及指定候选药物的临床试验的执行。将每种新药推向市场的成本超过20亿英镑，这在很大程度上是由于药物发现/开发过程中的严重损耗率（95%）。即使成功了，从实验室到病人，这个过程通常也需要12年左右的时间。因此，制药部门面临着提高生产力（通过减少成本和治疗病人的时间）和创新（通过寻找具有新作用方式和/或针对新疾病领域的药物）的重大挑战。生物活性小分子在药物发现过程中起着至关重要的作用。在选择特定蛋白质作为药物发现靶点之前，确定其在健康和疾病中的作用至关重要。在这些基础生物医学科学研究中，化学探针可以作为使能工具，允许建立蛋白质的细胞功能。从历史上看，对蛋白质生物学的探索非常不均衡，生物学家最喜欢研究的蛋白质在近20年来基本没有变化；然而，已经证明，化学探针的可用性可以对哪些蛋白质是生物医学研究的主题产生变革性影响。一旦选定了蛋白质靶点，就有必要发现一种安全有效的药物，以满足特定的医疗需求。超过90%的处方药和超过一半的新批准药物都是小分子药物。生物活性小分子的发现目前非常耗费资源，占药物发现总成本的20%左右（包括大多数最终失败的项目的成本）。分子发现通常是由候选分子的设计、制备和评估周期驱动的。这种方法通常可以一个接一个地研究一系列分子。为了加速发现，人们使用了一个狭窄的可靠化学反应工具包，这往往限制了被评估分子的多样性。通过这种中心对中心的合作，我们将开发一种发现生物活性小分子的新方法。发现过程将由所制备的分子的功能（“表型”）效应驱动。这将与目前压倒性的做法形成鲜明对比，在这种做法中，特定系列的分子在制备和评估之前就被设计出来。我们将有意利用在利兹大学（UoL）开发的反应，使数百种不同的分子能够并行制备。这些分子的表型效应将在马克斯普朗克分子生理学研究所（MPIMP）确定。生成功能性产品的反应将为使用RFI开发的算法设计数百种进一步反应提供信息。该方法将使自主搜索功能小分子成为可能，并且有可能改变药物化学（药物发现）和化学生物学（生物医学科学）。实现自主表型导向分子发现的雄心勃勃的目标只有通过整合合作中心的独特功能才有可能实现：片段/多样性导向合成（UoL），高通量实验（RFI），算法（RFI），表型筛选（MPIMP），化学蛋白质组学（UoL）和特定生物医学科学（MPIMP）。为了向最终用户展示新方法的价值，我们将证明它可以发现新的生物活性分子，例如化学探针，可以为支持疾病和/或健康衰老的生物机制提供新的见解。

The challenges associated with developing new medicines are very significant indeed. The process generally involves the selection of a protein target that is associated with a particular disease; the identification and optimisation of molecules that can modulate that target; and the execution of clinical trials involving a nominated drug candidate. The cost of bringing each new drug to the market is over £2 bn, in large part because of crippling (>95%) attrition rates in the drug discovery/development process. Even when successful, the process typically takes about 12 years from laboratory to patient. The pharmaceutical sector therefore faces the major challenges of increasing both productivity (by reducing costs and time to patient) and innovation (by finding drugs with new modes of action and/or for new disease areas).Bioactive small molecules can play crucial roles throughout the drug discovery process. Before a specific protein is selected as a drug discovery target, it is crucial to establish its role in both health and disease. In these fundamental biomedical science studies, chemical probes can serve as enabling tools that can allow the cellular function of proteins to be established. Historically, the biology of proteins has been explored very unevenly, and biologists' favourite proteins of study are largely unchanged in >20 years; however, it has been shown that the availability of chemical probes can have a transformative effect on which proteins are the subject of biomedical investigations. Once a protein target has been chosen, it is necessary to discover a safe and effective drug that allows a specific medical need to be addressed. Over 90% of prescribed medicines, and well over half of newly-approved drugs, are small molecules.The discovery of bioactive small molecules is currently very resource-intensive, contributing to around 20% of overall drug discovery costs (including the costs of the majority of programmes that ultimately fail). Molecular discovery is generally driven by cycles in which candidate molecules are designed, prepared and evaluated. This approach generally enables series of molecules to be investigated one-by-one. To expedite discovery, a narrow toolkit of reliable chemical reactions is used, which tends to limit the diversity of the molecules that are evaluated.Through this Centre-to-Centre collaboration, we will develop a new approach for discovering bioactive small molecules. The discovery process will be driven by the functional ("phenotypic") effect of the molecules that are prepared. It will contrast starkly with overwhelming current practice in which specific series of molecules are designed ahead of preparation and evaluation. We will deliberately harness reactions that have been developed at the University of Leeds (UoL) that will enable hundreds of diverse molecules to be prepared in parallel. The phenotypic effect of these molecules will be determined at the Max Planck Institute for Molecular Physiology (MPIMP). The reactions that yield functional products will inform the design of hundreds of further reactions using algorithms developed at RFI. The approach will enable the autonomous search for functional small molecules, and it has the potential to transform both medicinal chemistry (drug discovery) and chemical biology (biomedical science).The ambitious goal to realise autonomous phenotype-directed molecular discovery will only be possible by integrating the unique features of the collaborating Centres: fragment/diversity-oriented synthesis (UoL), high-throughput experimentation (RFI), algoithms (RFI), phenotypic screening (MPIMP), chemical proteomics (UoL) and specific biomedical science (MPIMP). To demonstrate the value of the new approach to end-users, we will demonstrate that it can enable the discovery of novel bioactive molecules, for example chemical probes that can provide new insights into biological mechanisms that underpin disease and/or healthy ageing.