Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70

HSP70 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.