The UK pharmaceutical industry loses billions each year when promising drug candidates fail in clinical trials because they bind to the wrong targets or have unsuitable properties. This project aims to fix that by developing a new strategy called constrained diversity-oriented synthesis—a way to efficiently create small molecules that stay within a desired range of chemical properties and binding profiles from the start. The core problem is that current methods produce molecules with too much random variation, many of which turn out to be useless as drugs. By restricting chemical diversity in a controlled way, the researchers hope to generate candidates that are more likely to succeed. If the approach works, it could transform how pharmaceutical companies discover new drugs, particularly for modulating protein-protein interactions—a difficult but promising area for treating diseases. The research is fundamental in nature, laying the scientific groundwork for a new tool in chemical biology. It does not promise an immediate treatment, but similar fundamental advances in synthetic chemistry have historically enabled entire classes of drugs.
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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.
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