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

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.

SUBMITTER: Cheeseman MD

PROVIDER: S-EPMC5371393 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

Cheeseman Matthew D MD Westwood Isaac M IM Barbeau Olivier O Rowlands Martin M Dobson Sarah S Jones Alan M AM Jeganathan Fiona F Burke Rosemary R Kadi Nadia N Workman Paul P Collins Ian I van Montfort Rob L M RL Jones Keith K

Journal of medicinal chemistry 20160511 10

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 h ...[more]

PMID: 27119979

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