Restricted Diversity; Constrained Diversity-Oriented Synthesis

英国在全球制药业处于领先地位，为许多疾病开发新药，并通过收入、就业、专业知识和重大投资使英国经济受益。英国制药业直接雇佣了大约7万人，通常为英国的GDP贡献100亿英镑。2007年的数据显示，该行业在英国的研究和开发方面总共投资了39亿英镑，英国的医药产品出口总额为146亿英镑，创造了43亿英镑的医药产品贸易顺差。这是一个需要学术研究支持的重要行业。该行业关注的是小分子的产生。药物是小分子。具有特殊性质或功能的小分子的发现对于影响日常生活的科学进步显然是重要的。不幸的是，在新药的开发中存在一个严重的问题。药物发现一直受到临床候选者的高损耗率的阻碍。这归因于临床候选药物没有正确的特性或结合谱。本提案旨在举例说明新的策略，以有效地获取和发现与制药工业直接相关的性能或结合谱范围内的新型小分子。这一战略被称为受限多样性导向综合。该项目将涉及新化学的发展、新小分子的合成、有限多样性的差异评估和发现生物活性化合物和潜在的化学治疗剂。该方法将为蛋白质-蛋白质相互作用调节的发展奠定科学和技术基础，作为化学生物学和分子治疗的工具。提出的工作有可能改变目前的药物发现方法，并从根本上扩展化学生物学可用的工具库。小分子在日常生活中是必不可少的。它们的重要性超出了制药业，因为塑料来源于小分子，碳氢化合物燃料也是小分子，等等。因此，我们的研究有可能对健康和生活质量产生广泛的影响。

The UK is at the forefront of the worldwide pharmaceutical industry, which develops new medicines for many diseases, and benefits the British economy through income, employment, expertise and major investment. The UK pharmaceutical industry directly employs around 70,000 people and typically contributes £10 billion to the UK's GDP. Figures for 2007 show that the industry invested a total of £3.9 billion in UK research and development, and that exports of pharmaceutical products from the UK totalled £14.6 billion, creating a trade surplus in pharmaceutical products of £4.3 billion. This is an important industry to support with academic research. The industry is concerned with the creation of small molecules. Pharmaceutical drugs are small molecules. The discovery of small molecules that have specific properties or functions is clearly important for scientific progress that will impact on everyday life. Unfortunately, there is a serious problem in the development of new drugs. Drug discovery has been hampered by a high rate of attrition of clinical candidates. This has been ascribed to the clinical candidates not having the correct properties or binding profiles.This proposal aims to exemplify new strategies to access efficiently and discover novel small molecules within a desired range of properties or binding profiles that are directly relevant to the pharmaceutical industry. This strategy has been termed constrained diversity-oriented synthesis. The project will involve the development of new chemistry, the synthesis of new small molecules, differential assessment of restricted diversity and the discovery of biologically active compounds and potential chemotherapeutic agents. The approach will lay the scientific and technological foundations for the development of protein-protein interaction modulation as a tool for chemical biology and molecular therapeutics. The proposed work has the potential to transform current approaches to drug discovery, and to radically extend the repertoire of tools available for chemical biology.Small molecules are essential to everyday life. They have importance beyond the pharmaceutical industry, since plastics derive from small molecules, hydrocarbon fuels are small molecules, etc. Therefore, our research has the potential to impact widely on health and quality of life.