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

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.