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Differences in conformational dynamics between Plasmodium falciparum and human Hsp90 orthologues enable the structure-based discovery of pathogen-selective inhibitors

Wang, Tai and Bisson, William H. and Mäser, Pascal and Scapozza, Leonardo and Picard, Didier. (2014) Differences in conformational dynamics between Plasmodium falciparum and human Hsp90 orthologues enable the structure-based discovery of pathogen-selective inhibitors. Journal of medicinal chemistry, 57 (6). pp. 2524-2535.

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Official URL: http://edoc.unibas.ch/dok/A6263111

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Abstract

The high sequence conservation of druggable pockets of closely related proteins can make it challenging to develop selective inhibitors. We designed a new drug discovery approach that exploits both the static and dynamic differences of two orthologues. We applied it, as a proof of concept, to identify compounds that discriminate between the molecular chaperone Hsp90 of the protozoan pathogen Plasmodium falciparum (Pf) and that of its human host. We found that the ATP-binding pocket has a Pf-specific extension, whose sequence lining is identical in human Hsp90 but which differs by tertiary structure and dynamics. Using these insights for a structure-based drug screen, we discovered novel 7-azaindole compounds that exclusively bind the recombinant N-terminal domain of PfHsp90 but not of human Hsp90 nor of a PfHsp90 mutant with "human-like" dynamics. Moreover, these compounds preferentially inhibit the growth of yeast complemented by PfHsp90 and block the growth of Pf in culture.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Mäser, Pascal
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
ISSN:0022-2623
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:12 Sep 2018 14:17
Deposited On:15 Aug 2014 07:16

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