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

用于预测小分子结晶的统计和高通量实验相结合的方法。

• 批准号: 2595838
• 金额: --
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2595838
• 关键词: combined; statistical; throughput; experimental; approach

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

阿斯利康的这一博士案例奖将专注于我们突破性的高通量封装纳米结晶技术的发展。目的是控制新药物样分子的固体形式，以提高生物利用度和物理性质。纽卡斯尔集团先前的工作已经导致了ENaCt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，并增强用于药物样分子结晶的高通量封装纳米级结晶技术方案，这是新药开发的关键一步。在Drs Hall和Probert的监督下，我将使用一组集中的药物样分子，完善ENaCt方法，根据分子的分子特性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。与博士堆我将实施增强的实验设计，这将允许统计分析的结果与构建预测结晶模型，其中实验条件可以从分子特性推导出的最终目标的应用，在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。通过研究它们的晶体结构，我将设计合成修饰以改善溶解度。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。我将在约翰逊和晶体学实验室作为一批博士/PDRA的一部分工作。我的角色将包括：开发和验证用于少量复杂小分子结晶的方法和自动化工具。建立测量自动化结晶方法成功率的新方法。开发预测算法，最大限度地提高结晶实验的成功率