Renwick, Suzanne Lynn (2022) A Generic Approach for Targeting Protein-Protein Interactions Using Multi-functional Piperazines. PhD thesis, University of Leeds.
Abstract
Protein-protein interactions (PPIs) play a pivotal role in most biological processes and misfunction in disease. PPIs have been considered challenging targets for modulation using small molecule ligands, due to their large, comparatively flat interfaces. Indeed, small molecule PPI inhibitors represent only a tiny fraction of current molecular therapeutics. α-Helix mediated PPIs are of particular interest given they have been observed in around 60% of PPIs and are potentially amenable to a common inhibitor strategy. This possible characteristic of PPIs could be advantageous when developing new tools or compounds for targeting these interactions. Example targets include p53/hDM2 and NOXAB/ MCL-1, which are important targets in oncology. A computational workflow (carried out by collaborators) was used to identify a number of generic small molecule scaffolds with the potential to be functionalised to target different α-helix mediated PPIs. Guided by the computational results, two libraries of bi-decorated piperazines were designed and subsequently synthesised by the author. Synthesis of decorated diazepanes was also explored but was not found to be suitable for efficient library synthesis. The synthesised piperazines were evaluated against p53/hDM2 and NOXA-B/MCL-1 using a combination of biophysical techniques including 15N-1H HSQC NMR spectroscopy and fluorescence anisotropy. The results from this screening, alongside further computational analysis, were used in the design of a more focussed library of tridecorated piperazines. These were synthesised and evaluated against the same targets in a similar way. Through this work, four compounds were identified with the potential for further development to low μM inhibitors, or at least a starting point for potential drug compound design. Overall, this integrated approach offers access towards discovery of novel, effective, low molecular weight PPI inhibitors, through combining several interdisciplinary work packages: computationally informed rational design; chemical synthesis of libraries of decorated small molecules; and biophysical screening using orthogonal assays.
Metadata
Supervisors: | Wilson, Andrew and Nelson, Adam |
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Keywords: | protein-protein interactions; PPIs; modulators; inhibitors; privileged scaffolds |
Awarding institution: | University of Leeds |
Academic Units: | The University of Leeds > Faculty of Maths and Physical Sciences (Leeds) > School of Chemistry (Leeds) |
Depositing User: | Dr Suzanne Renwick |
Date Deposited: | 23 Nov 2022 15:34 |
Last Modified: | 23 Nov 2022 15:34 |
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