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

Protein-protein interactions are essential for all living systems. The interactionsbetween tubulin dimers is already a broadly studied area, whereas the PDZ domaininteractions 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 ofmodulating the dynamics of the tubulin dimers or the interactions at PDZ domains.Forty three molecules were synthesised using indole, chalcone and piperidinepharmacophores. These molecules were evaluated either in silico or in vitro bystudying molecule-protein interactions by NMR and by measuring drug-tubulininteractions in order to identify lead molecules for potential pharmaceuticaldevelopment. Several interesting lead molecules are described. Compound 35 wasfound to be a potent inhibitor of microtubule assembly, whilst compounds 45 and 47were found to promote and stabilise the formation of microtubules. This observation isthe first described for this pharmacophore. Compound 45's activity was identified asbeing independent of binding to the Taxane domain. Compounds 40 and 41 were bothfound to capable of binding to a class I PDZ domain. These molecules will form thebasis of further studies aimed at developing novel anticancer therapies.Full experimental details for all syntheses and biological evaluations are reported

Level dc:type.qualificationlevel

Doctoral (Level 8)

Year dc:date.issued

2008

Author dc:creator

• Bennett, E

Language dc:language

en

Identifier

oai:salford-repository.worktribe.com:1337262

OAI identifier oai:identifier

oai:salford-repository.worktribe.com:1337262