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J Med Chem. 2016 May 26;59(10):4625-36. doi: 10.1021/acs.jmedchem.5b02001. Epub 2016 May 11.

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

Author information

1
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, U.K.
2
Division of Structural Biology, The Institute of Cancer Research , London SW7 3RP, U.K.

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.

PMID:
27119979
PMCID:
PMC5371393
DOI:
10.1021/acs.jmedchem.5b02001
[Indexed for MEDLINE]
Free PMC Article

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