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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2016 Apr 28

PMID 27119979

Citations 17

Authors

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

Affiliations

Soon will be listed here.

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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