Integrated computational and synthetic tools to drive the discovery of orthosteric protein-protein interaction inhibitors

小分子药物继续主导着我们治疗疾病的集体能力。然而，制药行业面临着几个方面的挑战，提高生产率已被视为该行业的重大挑战。在医疗保健系统成本日益受限的背景下，推出新药的成本越来越高（最近估计每种新药的成本为18亿英镑！）。为了提高药物发现的生产力，有必要开发创新的新药，以解决目前未得到满足的医疗需求。蛋白质-蛋白质相互作用为治疗包括癌症、炎症性疾病、心血管疾病和感染在内的疾病提供了一个重要的尚未开发但具有挑战性的机会。药物通过与体内靶蛋白结合而起作用。大多数现有的小分子药物都与蛋白质中定义明确的口袋结合在一起——类似于钥匙可以插入锁中。与之形成鲜明对比的是，设计抑制蛋白质-蛋白质相互作用的药物通常需要一种完全不同类型的药物与蛋白质目标的相互作用——类似于一只手抓住一个球。因此，针对蛋白质-蛋白质相互作用的有效药物的开发提出了未来药物发现需要满足的新挑战。该计划将开发新的工具和理解，这将促进未来针对蛋白质-蛋白质相互作用的药物发现。我们将开发计算工具，根据它们潜在的3D结构和它们可以被小分子抑制的概率来分类蛋白质-蛋白质相互作用。然后，我们将利用这些计算工具来设计小分子的类别，这些小分子可以使用最先进的合成方法很容易地制备，并且倾向于针对不同类型的蛋白质-蛋白质相互作用。由此产生的小分子抑制剂将提供给生物学研究人员，以帮助了解蛋白质-蛋白质相互作用在疾病中的作用。此外，这些新工具将为研究界提供便利，以促进针对蛋白质-蛋白质相互作用的小分子药物的早期发现。该计划将受益于大型制药公司、较小的药物发现公司、一个非营利性药物发现组织和国际学者的投入。广泛的专家参与是必不可少的，因为越来越多的趋势是由一系列组织（包括工业界和学术界）进行早期药物发现，特别是对于更具挑战性的目标类别。因此，与更广泛的研究社区合作，我们将确保满足针对蛋白质-蛋白质相互作用的早期药物发现所需的未来能力。

Small molecule drugs continue to dominate our collective ability to treat disease. However, the pharmaceutical industry faces challenges on several fronts, and increasing productivity has been framed as the grand challenge for the sector. Against a background of increasingly cost-constrained healthcare systems, the cost of launching new drugs is increasingly high (recently estimated at £1.8 Bn for each new drug!). In order to improve productivity in drug discovery, it is necessary to develop innovative new medicines that address currently unmet medical needs. Protein-protein interactions represent a significant untapped, but challenging, opportunity for treating diseases including cancer, inflammatory disease, cardiovascular disease and infection.Drugs function by binding to a protein target within the body. Most existing small molecule drugs bind to well-defined pockets in proteins - analogous to a key fitting into a lock. In stark contrast, the design of drugs to inhibit protein-protein interactions generally requires a fundamentally different type of interaction of the drug with its protein target - analogous to a hand gripping a ball. Thus, the development of effective drugs that target protein-protein interactions raises new challenges that need to be met in future drug discovery. This programme will develop new tools and understanding that will facilitate future drug discovery against protein-protein interactions.We will develop computational tools to classify protein-protein interactions according to their underlying 3D structure and the probability that they can be inhibited using small molecules. We will then exploit these computational tools to design classes of small molecule that can be prepared readily using state-of-the-art synthetic methods, and that are predisposed to target different types of protein-protein interaction. The resulting small molecule inhibitors will be made available to biological researchers to help understand the role of protein-protein interactions in disease. In addition, the new tools will be made accessible to the research community to facilitate the early-stage discovery of small molecule drugs that target protein-protein interactions. The programme will benefit from the input of major pharmaceutical companies, smaller drug discovery companies, a not-for-profit drug discovery organisation, and international academics. The involvement of a wide range of experts is essential because of the increasing trend for early stage drug discovery to be conducted by a range of organisations (both industry and academic), especially for more challenging target classes. Thus, together with wider research community engagement, we will ensure that the required future capabilities for early-stage drug discovery against protein-protein interactions are met.