Software, Synthesis and Screening: cheminformatic led invention, design and synthesis of novel compounds for the treatment of septic shock

感染性休克是一种感染并发症，会导致危险的低血压。在英国，脓毒症每年影响150,000名不同年龄段的患者，在一些患者群体中死亡率约为50%。脓毒症反应是由循环细菌的存在引发的，引起主要的全身炎症反应综合征(SIRS)，导致一系列危及生命的后果。最严重的问题之一是循环中的肾上腺髓质素升高，这是一种激素，会导致血管通透性增加和血管扩张，导致血流灌注减少和器官衰竭。肾上腺髓质素在感染性休克中的作用涉及与细菌细胞壁蛋白的相互作用，刺激患者体内的细胞因子风暴。因此，肾上腺髓质素是感染性休克/SIRS治疗的既定靶点。肾上腺髓质素有三个密切相关的异构体受体CGRP、AM1和AM2，其中两个已经进行了药物开发研究。具体地说，CGRP抑制导致了偏头痛的治疗，而我们的团队开发了AM2抑制剂用于治疗胰腺癌。在这个项目中，我们将针对AM1，以期防止肾上腺髓质素促进血压下降。目前，一种抗AM1的单抗(Adrecizumab)正在启动感染性休克的II期试验，该试验在临床前取得了很好的结果。此外，一种截短的肾上腺髓质素多肽作为一种竞争性激素拮抗剂正在开发中。然而，抗体在系统中停留的时间很长，而多肽的寿命很短。这两种药物的制造成本都很高，而且很难储存，因此具有适当设计的半衰期的小分子AM1受体拮抗剂将具有相当大的优势。小分子疗法继续受到药物研发界的高度重视。计算能力的提高和药物开发成本的增加意味着现在的努力集中在“智能”的发现过程上。因此，利用现有的AM1 X射线晶体结构，我们将结合建模和化学信息学方法，通过分子匹配对分析来确定具有产生生物活性化合物的潜力的新的化学空间。机器学习将识别与生物活性相关的关键特征，并将这些特征构建到分子设计中。他们将生产一个适用于生物筛选的小型化合物库，这将为新药发现合作(谢菲尔德大学拥有的知识产权)提供种子。与利兹大学和谢菲尔德大学的分支机构红砖分子公司的合作意味着，通过销售新型化学成分的目录，更广泛的制药研发社区将能够接触到这种新型化学物质。

Septic shock is a complication of infection that leads to dangerously low blood pressure. In the UK, sepsis affects >150,000 patients annually across the age range, and death rates are ~50% in some patient groups. The sepsis response is triggered by the presence of circulating bacteria which initiate a major Systemic Inflammatory Response Syndrome (SIRS) leading to a range of life threatening consequences.One of the most acute problems is an elevation of circulating adrenomedullin, a hormone which causes increased permeability of blood vessels and vasodilatation leading to reduced perfusion and organ failure. Adrenomedullin's role in septic shock involves an interaction with a bacterial cell wall protein, stimulating a cytokine storm in the patient. Accordingly, adrenomedullin is an established target for treatment in septic shock/SIRS. Adrenomedullin has three closely related heteromeric receptors CGRP, AM1 and AM2 and two of these have been subject to drug development studies. Specifically, CGRP inhibition has led to treatments for migraine while our team has developed AM2 inhibitors for the treatment of pancreatic cancer. In this programme, we will target AM1 with a view to preventing adrenomedullin promoted reduction in blood pressure. Currently, a monoclonal antibody (Adrecizumab) to AM1 is starting phase II trials for septic shock after strong preclinical results. In addition, a truncated adrenomedullin peptide is in developmentas a competitive hormone antagonist. However, antibodies remain in the system for long periods, and peptides are short-lived. Both are costly to manufacture and hard to store, so a small molecule AM1 receptor antagonist with an appropriately engineered half-life would have considerable advantages.Small molecule therapeutics continue to receive significant attention from the pharmaceutical R&D community. Improvements in computing power and increasing costs of drug development mean that efforts are now focused on 'intelligent' discovery processes. Accordingly, using an existing AM1 X-ray crystal structure, we will combine modelling and cheminformatics methods to identify novel chemical space with potential to generate biologically-active compounds using Molecular-matched pair analysis. Machine learning will identify key features associated with bioactivity and build these features into molecular design. They will produce a small library of compounds suitable for biological screening that will seed a new drug discovery collaboration (IP owned by Uni of Sheffield). Partnering with Redbrick Molecular, a spinout from Universities of Leeds and Sheffield, means that the novel chemistry will be accessible to the broader pharmaceutical R&D community through catalogue sales of novel chemical building blocks.