3D Libraries Consortium

"Fragment-based" drug discovery is a successful and established approach in which potential drug targets (usually enzymes) are screened with very small molecules or fragments to find new chemical start points for drug discovery programmes. Fragments usually bind quite weakly to their target as being small they can only form a few points of interaction. However, their size allows them to find the optimum orientation in which to bind. These fragments can then be optimised by growing them to build up additional interactions. This process is usually guided by X-ray crystallography derived information on the how the fragment binds to the target and where additional beneficial interactions could be obtained. By this approach, it is possible to optimise the weakly binding fragment into a potent enzyme inhibitor in a very timely and efficient manner. This technique has been successfully used to design and develop a number of drug molecules that are now in clinical development. The UK has been a leader in this field and several successful companies based on this approach have been established.

Most of the collections (or libraries) of fragments that have been developed are based around flat molecules. Whilst this has proved a very successful approach for some drug targets, this approach has not worked well for others, particularly some of the newer and complex drug targets emerging from basic biology research. An example of this are compounds which could block specific protein - protein interactions, as they could have tremendous potential as therapeutic agents, but which have proven difficult to tackle using traditional BioPharma screening collections. Therefore, we will seek to extend "fragment-based" drug discovery to drug targets such as protein - protein interactions by developing 3-dimensional fragment libraries. A number of not-for-profit drug discovery and academic groups within the UK have come together with the aim of developing these libraries. This consortium will bring together expertise in designing and developing efficient ways of making the molecules, to deliver the most appropriate libraries, with the greatest chance of providing high quality chemical start points for drug discovery and tools to develop the understanding of novel biology.

We are applying for the Collaborative Network Grant to support a number of activities. Firstly, it will help facilitate the interactions between members of our consortium to maximise the potential synergies derived from the groups working together. Secondly, it will help us to engage with other scientists within the UK to expand the capabilities and expertise of the consortium. This will include engagement with i) computational chemists and chemoinformaticians to design the libraries and seek ways in which the studies can help develop their computational platforms, ii) chemistry departments within the UK where there is wealth of knowledge of novel organic chemistry methodology and technology, to utilise their knowledge to prepare novel 3-dimensional libraries iii) biologists, working in UK universities to use these libraries to translate some of their frontier breaking biology into novel drug targets by providing the "chemical tools" needed to help understand the biology.

Within the grant, we are applying for a project manager, who will be able to drive the project forward, by facilitating interactions between the current and future members of the consortium, through meetings and symposia; coordinating the work of the consortium to ensure best use of resources and writing funding applications to help resource the design and production of the 3-dimensional libraries. We are also applying for funding for travel to meetings for both the project manager and consortium members.

This unique consortium in pulling together such a broad range of UK organisations and disciplines to deliver a focussed objective will have an impact across commercial, charitable and academic sectors. The activities and outputs of the consortium will lead to new treatments for diseases resulting in both societal and economic benefits for the UK and generation of new knowledge across multiple disciplines.

The UK is already a leader in the field of fragment-based drug discovery. This co-ordinated approach to 3D fragment libraries would help to maintain and improve this competitive advantage, through the development of new paradigms that could be employed by these companies. In addition, chemical synthesis companies could be involved in manufacturing and selling the libraries.

There is an urgent need for the development of new drugs for many diseases, e.g. diabetes, cancer and Alzheimer's disease. New treatments for these diseases would have huge implications for society through improvements in quality of life and reduced health care burden on the economy. These libraries would facilitate the development of new drugs to treat these diseases and new tools to understand the basic biology underpinning them. Discovery of new drugs would have significant wealth generating benefits for the UK economy e.g. (i) out-licensing of discoveries made, leading to inward investment into the organisations; (ii) potential for the development of new companies, to exploit the discoveries made; (iii) development and marketing of new therapies by UK-based BioPharma companies.

There are many novel potential drug targets being discovered through exciting world-class biology research. Chemical tools are proving increasingly important in understanding these biological systems and development of new strategies for improvement of human health. The design and discovery of these tools will be greatly facilitated by high quality 3D fragment libraries. During the process of the library design, we will develop new computational methods and chemoinformatics tools, which will have application more widely than the 3D libraries project.
The UK is also one of the leading nations for drug discovery organizations outside of the BioPharma sector. These 3D-libraries would help these organisations to maintain their world-leading positions, address their remit of tackle novel drug targets, and produce new intellectual property and medicines.

Furthermore, within members of the consortium, there is a strong alignment with the UK's commitment to better healthcare and support for developing countries. These neglected tropical diseases cause very high levels of mortality, morbidity and economic impact mainly within the developing world. Development of these much-needed drugs will be facilitated in this resource limited area, as the use of the fragment-based approach can be a more cost effective way of tackling drug targets compared to using high throughput screening approaches.

The BioPharma industry is a major contributor to the UK economy. Therefore, it is important scientists are trained to have expertise in all aspects of drug discovery and retained in the UK, to encourage companies to set up or relocate to the UK. The 3D libraries consortium will help this training process. This will include chemists who are employed directly to make 3D libraries and at the consortium organisations, as they will be engaged in thinking through and developing novel strategies for drug and chemical tool discovery. It will expose academic synthetic organic chemists to the drug discovery process and medicinal chemistry, educating them in this field. Further, computational chemists and chemoinformaticians will gain experience of developing methodology in their field, but importantly they will be working closely with expert drug discovers, developing their knowledge more broadly.