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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 26, 2016
• 年：2016
• 卷：59
• 期：10
• 页码：4625-4636
• 全文大小：621K
• 年卷期：0
• ISSN：1520-4804

文摘

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.