Enhancing early stage drug discovery using a transformative approach to crystal structure determination

Crystal structures provide knowledge of both the 3-dimensional shapes of drug development compounds and how to improve a compound’s physical properties (e.g. solubility). This knowledge is useful at all stages of a drug development programme, from hit identification through to lead optimisation and beyond into formulation. In many cases, it is not possible to grow large enough single crystals of the compounds, preventing the use of single-crystal X-ray studies. In such cases, crystalline powders can still be obtained and powder X-ray diffraction can be used to allow crystal structure determination from powder data. The problem often encountered here, however, is the requirement of around 25-50 mg of material. Such amounts are simply not available until the choice of lead compound for the programme has already been made. Therefore, crystal structures obtained by SDPD come too late in the drug development process to influence crucial early decision-making.
The aim of this PhD project is to develop new methodologies for crystal structure determination from powder diffraction data using very small amounts of material, suitable for adoption by industry at the very beginning of a drug discovery programme. The work is ambitious, involving crystallisation, crystallography, data analysis and (potentially) software development. The successful candidate, based at the University of Reading (but also spending time at C4X Discovery in Manchester), will emerge with a set of skills highly relevant to academia and industry