Exploiting protein conformational change to optimize adenosine-derived inhibitors of HSP70

Research output: Contribution to journalArticlepeer-review


  • Matthew D. Cheeseman
  • Isaac M. Westwood
  • Olivier Barbeau
  • Martin Rowlands
  • Sarah Dobson
  • Fiona Jeganathan
  • Rosemary Burke
  • Nadia Kadi
  • Paul Workman
  • Ian Collins
  • Rob L M Van Montfort
  • Keith Jones

Colleges, School and Institutes


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.


Original languageEnglish
Pages (from-to)4625-4636
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number10
Early online date27 Apr 2016
Publication statusPublished - 26 May 2016