Open AccessExploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70
Author(s) -
Matthew D. Cheeseman,
Isaac M. Westwood,
Olivier Barbeau,
Martin Rowlands,
S.E. Dobson,
Alan M. Jones,
Fiona Jeganathan,
Rosemary Burke,
Nadia Kadi,
Paul Workman,
Ian Collins,
Rob L. M. van Montfort,
Keith Jones
Publication year - 2016
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.5b02001
Subject(s) - chemistry , hsp70 , chaperone (clinical) , adenosine , heat shock protein , drug discovery , conformational change , mechanism of action , biochemistry , biophysics , computational biology , in vitro , medicine , pathology , biology , gene
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.
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