Modulating protein-protein interactions : novel inhibitors of PDZ domains and tubulin dynamics

Bennett, E 2008, Modulating protein-protein interactions : novel inhibitors of PDZ domains and tubulin dynamics , PhD thesis, University of Salford.

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Abstract

Protein-protein interactions are essential for all living systems. The interactions between tubulin dimers is already a broadly studied area, whereas the PDZ domain interactions is a relatively recent area of study. The literature in these areas is reviewed. This research project designed and synthesised novel molecules which were capable of modulating the dynamics of the tubulin dimers or the interactions at PDZ domains. Forty three molecules were synthesised using indole, chalcone and piperidine pharmacophores. These molecules were evaluated either in silico or in vitro by studying molecule-protein interactions by NMR and by measuring drug-tubulin interactions in order to identify lead molecules for potential pharmaceutical development. Several interesting lead molecules are described. Compound 35 was found to be a potent inhibitor of microtubule assembly, whilst compounds 45 and 47 were found to promote and stabilise the formation of microtubules. This observation is the first described for this pharmacophore. Compound 45's activity was identified as being independent of binding to the Taxane domain. Compounds 40 and 41 were both found to capable of binding to a class I PDZ domain. These molecules will form the basis of further studies aimed at developing novel anticancer therapies. Full experimental details for all syntheses and biological evaluations are reported

Item Type:	Thesis (PhD)
Contributors:	Ducki, S (Supervisor) and Hadfield, JA (Supervisor)
Schools:	Schools > School of Environment and Life Sciences
Depositing User:	Institutional Repository
Date Deposited:	16 Aug 2021 13:28
Last Modified:	04 Aug 2022 11:22
URI:	https://usir.salford.ac.uk/id/eprint/61570

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