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Details of Grant 

EPSRC Reference: EP/P016618/1
Title: The Realisation of Fragment-Oriented Synthesis
Principal Investigator: Marsden, Professor SP
Other Investigators:
Nelson, Professor AS
Researcher Co-Investigators:
Project Partners:
Astex Therapeutics Diamond Light Source University of Manchester, The
Department: Sch of Chemistry
Organisation: University of Leeds
Scheme: Standard Research
Starts: 08 May 2017 Ends: 07 May 2020 Value (£): 574,490
EPSRC Research Topic Classifications:
Chemical Synthetic Methodology
EPSRC Industrial Sector Classifications:
Pharmaceuticals and Biotechnology
Related Grants:
Panel History:
Panel DatePanel NameOutcome
25 Oct 2016 EPSRC Physical Sciences - October 2016 Announced
Summary on Grant Application Form
Despite the rise of biological therapies, the discovery of new and improved medicinal agents to treat disease is still dominated by small molecules. The challenges in discovering a new molecular medicine are significant indeed - typically taking about 12 years from laboratory to patient, and costing of the order of $2 bn for each new drug. As a result, the pharmaceutical industry is continually looking for new approaches to improve the efficiency and productivity of the drug discovery process.

The binding of a drug to its target protein can be likened to the fitting of a key into a lock, and the design of molecular 'keys' that have the appropriate arrangements of teeth and grooves to complement the 'lock' of the protein binding site is a major challenge - particularly when one considers that the protein binding sites (and hence the molecules that need to interact with them) are generally highly complex and three-dimensional in shape. One approach to this problem, that has become increasing important over the last 15-20 years, is fragment-based drug discovery (FBDD). Here, the drug discovery process begins with fragments: very small molecules that are broadly analogous to an individual groove or tooth motif of a key. Fragments are then grown iteratively (to add more grooves and/or teeth) until promising larger and tighter-binding molecules are obtained. Although a relatively new approach, this method has already resulted in medicines that are being used clinically, for example against cancer.

Despite the remarkable rise of FBDD, significant chemical challenges for the field have been identified by industry. For example, limitations in the synthetic chemistry toolkit mean that growth of fragments is much easier in some directions that others. We will therefore expand this toolkit to enable efficient the growth of fragments in many different directions. Crucially, we will demonstrate that our fragment-oriented synthesis (FOS) toolkit can drive the discovery of ligands for pharmaceutically-relevant proteins. To ensure alignment with future discovery needs, we will collaborate with a pharmaceutical company that specialises in FBDD. We will ensure that our FOS toolkit becomes embedded in different types of drug discovery organisations to maximise the impact of the work.
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