Development of quantitative analysis methods to accelerate the optimisation of fragment hits to lead compounds using NMR spectroscopy

基于片段的药物发现（FBDD）是一种广泛使用的方法，用于生成药物发现的起点和化学生物学的工具，但一个重要的瓶颈是在对化合物进行结合评估之前，从最初的攻击中开发的化合物进行耗时和劳动密集型的纯化。为了消除这一瓶颈，Vernalis开发了脱除率筛选（ORS）来筛选未纯化的粗反应混合物（CRM），利用SPR观察到的解离率降低作为CRM中高亲和粘合剂的信号。然而，这种方法仅限于FBDD的晚期，在那里配体解离速率已经相对较慢。该项目旨在开发新的实验和分析方法，通过使用先进的核磁共振波谱和线形分析方法，将ORS扩展到与弱结合片段相关的更快的时间尺度，从而加快FBDD管道的早期阶段。在这一阶段设想了两个主要目标，并将根据所产生的结果视需要加以改进：研究和评估1D和2D蛋白质观察（PO）和1D配体观察（LO）核磁共振实验的能力，采用1H或19F检测，筛选慢解离配体的CRMs。开发和验证开源软件分析工具，与TITAN线形分析软件和/或Vernalis KNIME工作流集成，实现易于使用和访问的软件包中开发的分析。该项目显然符合MRC的职责范围：培训熟练的研究人员开发新技术，加速新药物的发现，解决对我们的工业合作伙伴特别重要的问题，从而通过开发的专有技术提高他们的经济竞争力，并最终通过改进新药物的开发来提高生活质量。该项目与疾病基本机制DTP主题一致，应用结构生物学和生物物理学方法更好地了解小分子与疾病相关大分子的相互作用，简化和加速药物发现过程。学生将接受各种定量技能的培训，特别是数学、计算和数据分析，而拟议的项目是高度跨学科的：核磁共振方法的开发需要理解量子统计力学，这将与经典化学动力学和热力学、计算分析和软件工程、分子生物学和生物物理技能相结合。

Fragment-based drug discovery (FBDD) is a widely used approach to generate starting points for drug discovery and tools for chemical biology, but a significant bottleneck is time-consuming and labour intensive purification of compounds developed from an initial hit, before they can be evaluated for binding. To eliminate this bottleneck, off-rate screening (ORS) has been developed by Vernalis to screen unpurified crude reaction mixtures (CRMs), using reductions in dissociation rate observed by SPR as a signal of a high affinity binder within a CRM. However, this approach is limited to late stages of FBDD, where ligand dissociation rates are already relatively slow.This project aims to develop new experimental and analytical approaches to accelerate early stages of FBDD pipelines, by using advanced NMR spectroscopy and lineshape analysis methods to extend ORS to faster timescales associated with weak-binding fragments.Two primary objectives are envisaged at this stage, to be refined as necessary according to the results that are generated:1. Investigate and assess the capacity for 1D and 2D protein-observed (PO) and 1D ligand-observed (LO) NMR experiments, employing 1H or 19F detection, to screen CRMs for slow-dissociating ligands.2. Develop and validate open-source software analysis tools, integrated with TITAN lineshape analysis software and/or Vernalis KNIME workflows, that implement the analyses developed in easy-to-use and accessible packages.This project is a clear fit to the MRC remit: training a skilled researcher to develop new technologies that will accelerate the discovery of new medicines, addressing a problem of particular importance to our industrial partner and so improving their economic competitiveness through the know-how that will be developed, and ultimately contributing to improvements in the quality of life by improving the development of new drugs. The project is aligned with the Fundamental Mechanisms of Disease DTP theme, applying structural biology and biophysical methods to better understand interactions of small molecules with disease-relevant macromolecules, streamlining and accelerating the process of drug discovery. The student will be trained in a variety of quantitative skills, particularly mathematics, computation and data analytics, while the proposed project is highly interdisciplinary: NMR method development demands an understanding of quantum statistical mechanics, which will be coupled with classical chemical kinetics and thermodynamics, computational analysis and software engineering, and molecular biology and biophysical skills.