A combined statistical and high-throughput experimental approach for the predictive crystallization of small molecules.

这项与阿斯利康合作的博士案例奖将聚焦于我们突破性的高通量封装纳米结晶技术的开发。目的是控制新的类药物分子的固体形式，以提高生物利用度和物理性质。纽卡斯尔小组之前的工作已经导致了ACT的开发，为自动纳米级结晶提供了第一个平台技术。在这个项目中，我将与以McCabe博士为首的阿斯利康结晶学小组合作，进一步开发这项技术，并增强用于类药物分子结晶的高通量封装纳米结晶技术协议，这是新药开发的关键一步。在DRS Hall和Probert的监督下，我将与一组集中的类药物分子一起工作，完善颁布方法，根据分子的性质为分子提供优化的结晶条件。通过使用高通量机器人技术，我将开发用于实验设置和结果分析的自动化工作流程。与Dr Heaps I合作，我将实施增强的实验设计，允许将统计分析应用于结果，最终目标是构建一个预测结晶模型，在该模型中，实验条件可以从分子性质推导出来，这是该领域迄今尚未解决的挑战。有了这些工具，我将把这些方法应用于早期药物分子。通过对它们晶体结构的研究，我将设计合成修饰来改善溶解度分布。这将在药物开发过程中更早地考虑生物利用度，从而降低药物失败率并加快上市时间。我将作为约翰逊实验室和结晶学实验室博士/PDRA的一部分工作。我的职责将包括：开发和验证方法，以及少量复杂小分子结晶的自动化工具。建立测量自动结晶方法成功率的新方法。开发最大限度提高结晶实验成功率的预测算法

This PhD CASE award with AstraZeneca will focus on the development of our ground breaking high throughput Encapsulated Nanoscale Crystallization technology. With the aim to control the solid form of new drug-like molecules to have improved bioavailability and physical properties. Previous work by the Newcastle group has resulted in the development of ENaCt, providing the first platform technology for automated nanoscale crystallization. In this project I will work with the crystallography group of AstraZeneca, headed by Dr McCabe, to further develop the technique and enhance the high-throughput Encapsulated Nanoscale Crystallization technology protocols for the crystallisation of drug-like molecules, a key step in new drug development. Working with a focussed set of drug-like molecules, under the supervision of Drs Hall and Probert, I will refine the ENaCt methodologies to provide optimised crystallisation conditions for molecules based on their molecular properties. Through the use of high-throughput robotics I will develop automated work flows for both experimental setup and outcome analysis. Working with Dr Heaps I will implement enhanced experimental design that will allow the application of statistical analysis to the outcomes with the final aim of constructing a predictive crystallisation model in which experimental conditions can be deduced from molecular properties, an as yet unaddressed challenge in the field. With these tools in hand I will apply these methods to early stage drug molecules. Through the investigation of their crystal structures I will design synthetic modifications to improve solubility profiles. This will bring the consideration of bioavailability much earlier in the drug development process thus decreasing drug failure rates and speeding time to market. I will work as part of a cohort of PhDs/PDRAs in the Johnson and Crystallography laboratories. My roles will include: Developing and validating methods, and automated tools for the crystallisation of small quantities of complex small molecules.Establishing novel methods for measuring the success rates of automated crystallisation methods.Development of predictive algorithms that maximise the success rates of crystallisation experiments