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

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 Jones

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

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
Volume59
Issue number10
Early online date27 Apr 2016
DOIs
Publication statusPublished - 26 May 2016

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