Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70
dataset
posted on 2016-04-27, 00:00 authored by Matthew
D. Cheeseman, Isaac M. Westwood, Olivier Barbeau, Martin Rowlands, Sarah Dobson, Alan M. Jones, Fiona Jeganathan, Rosemary Burke, Nadia Kadi, Paul Workman, Ian Collins, Rob L. M. van
Montfort, Keith JonesHSP70 is a molecular
chaperone and a key component of the heat-shock
response. Because of its proposed importance in oncology, this protein
has become a popular target for drug discovery, efforts which have
as yet brought little success. This study demonstrates that adenosine-derived
HSP70 inhibitors potentially bind to the protein with a novel mechanism
of action, the stabilization by desolvation of an intramolecular salt-bridge
which induces a conformational change in the protein, leading to high
affinity ligands. We also demonstrate that through the application
of this mechanism, adenosine-derived HSP70 inhibitors can be optimized
in a rational manner.
