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

此次与阿斯利康的博士案例奖将重点关注我们突破性的高通量封装纳米级结晶技术的发展。目的是控制固体形式的新型药物样分子，以提高生物利用度和物理性质。纽卡斯尔小组之前的工作导致了ENaCt的发展，为自动化纳米级结晶提供了第一个平台技术。在这个项目中，我将与由McCabe博士领导的阿斯利康晶体学小组合作，进一步开发该技术，并增强用于药物类分子结晶的高通量封装纳米级结晶技术协议，这是新药开发的关键一步。在Hall博士和Probert博士的监督下，我将与一组重点药物样分子合作，改进ENaCt方法，根据分子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，我将为实验设置和结果分析开发自动化工作流程。与希普斯博士合作，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性结晶模型，其中实验条件可以从分子性质中推断出来，这是该领域尚未解决的挑战。有了这些工具，我将把这些方法应用于早期药物分子。通过对其晶体结构的研究，我将设计合成改性来改善溶解度。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。我将在约翰逊实验室和晶体学实验室作为博士/PDRAs的一员工作。我的角色将包括：开发和验证方法，以及用于小批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。开发预测算法，使结晶实验的成功率最大化

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