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

晶体结构提供了药物开发化合物的三维形状以及如何改善化合物的物理性质（例如溶解度）的知识。这些知识在药物开发计划的所有阶段都很有用，从命中识别到领先优化，再到制定。在许多情况下，不可能生长足够大的化合物单晶，从而阻止了单晶X射线研究的使用。在这种情况下，仍然可以获得结晶粉末，并且可以使用粉末X射线衍射来允许从粉末数据确定晶体结构。然而，这里经常遇到的问题是需要大约25-50 mg的材料。在为该方案选择了先导化合物之前，根本无法获得这样的数量。因此，SDPD获得的晶体结构在药物开发过程中来得太晚，无法影响关键的早期决策。该博士项目的目的是开发新的方法，使用非常少量的材料从粉末衍射数据中确定晶体结构，适合在药物发现计划的最初阶段被行业采用。这项工作是雄心勃勃的，涉及结晶，晶体学，数据分析和（潜在的）软件开发。成功的候选人，总部设在阅读大学（但也花时间在曼彻斯特的C4 X发现），将出现一套与学术界和工业界高度相关的技能

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