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

Bennett, E

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

• Thesis Type: Thesis
• Deposit Date: Aug 16, 2021
• Award Date: Dec 1, 2008