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

Cheeseman, MD and Westwood, IM and Barbeau, O and Rowlands, M and Dobson, S and Jones, AM and Jeganathan, F and Burke, R and Kadi, N and Workman, P and Collins, I and van Montfort, RL and Jones, K (2016) Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70. Journal of Medicinal Chemistry, 59.

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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.

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