Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70.
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Authors
Cheeseman, MD
Westwood, IM
Barbeau, O
Rowlands, M
Dobson, S
Jones, AM
Jeganathan, F
Burke, R
Kadi, N
Workman, P
Collins, I
van Montfort, RLM
Jones, K
Westwood, IM
Barbeau, O
Rowlands, M
Dobson, S
Jones, AM
Jeganathan, F
Burke, R
Kadi, N
Workman, P
Collins, I
van Montfort, RLM
Jones, K
Document Type
Journal Article
Date
2016-05-26
Date Accepted
2016-04-26
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.
Citation
Journal of medicinal chemistry, 2016, 59 (10), pp. 4625 - 4636
Source Title
Publisher
AMER CHEMICAL SOC
ISSN
0022-2623
eISSN
1520-4804
Collections
Research Team
Medicinal Chemistry 2
Medicinal Chemistry 3
Hit Discovery & Structural Design
Medicinal Chemistry 3
Hit Discovery & Structural Design