Differences in Conformational Dynamics between Plasmodium falciparum and Human Hsp90 Orthologues Enable the Structure-Based Discovery of Pathogen-Selective Inhibitors

Article Article scientifique Article Differences in Conformational Dynamics between Plasmodium falciparum and Human Hsp90 Orthologues Enable the Structure-Based Discovery of Pathogen-Selective Inhibitors eng 2014 author Wang Tai 655798 author Bisson William Henry 714830 author Mäser Pascal author Scapozza Leonardo 600318 author Picard Didier 0000-0001-8816-9668 26830 2524-2535 10.1021/jm401801t 24580531 0022-2623 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. Dewey 570 Dewey 615 46 Département de biologie cellulaire 165 31 Section des sciences pharmaceutiques 17 false 838 Groupe Picard Journal of medicinal chemistry 57 6 6cd21c22-206f-49c2-ae42-884687c051f7 Article (Published version) Public jm401801t.pdf 3500942 application/pdf Private 2015-04-17 openAccess Faculté des sciences / Section de biologie / Département de biologie cellulaire Faculté des sciences / Section des sciences pharmaceutiques

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Differences in Conformational Dynamics between Plasmodium falciparum and Human Hsp90 Orthologues Enable the Structure-Based Discovery of Pathogen-Selective Inhibitors	Journal of medicinal chemistry			2014	724	792

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Bisson, William Henry