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dc.contributor.authorMoroni, Elisabetta
dc.contributor.authorZhao, Huiping
dc.contributor.authorBlagg, Brian S. J.
dc.contributor.authorColombo, Giorgio
dc.date.accessioned2017-05-16T18:55:35Z
dc.date.available2017-05-16T18:55:35Z
dc.date.issued2014-01-27
dc.identifier.citationMoroni, E., Zhao, H., Blagg, B. S. J., & Colombo, G. (2014). Exploiting conformational dynamics in drug discovery: design of C-terminal inhibitors of Hsp90 with improved activities. Journal of Chemical Information and Modeling, 54(1), 195–208. http://doi.org/10.1021/ci4005767en_US
dc.identifier.urihttp://hdl.handle.net/1808/24228
dc.description.abstractThe interaction that occurs between molecules is a dynamic process that impacts both structural and conformational properties of the ligand and the ligand binding site. Herein, we investigate the dynamic cross-talk between a protein and the ligand as a source for new opportunities in ligand design. Analysis of the formation/disappearance of protein pockets produced in response to a first-generation inhibitor assisted in the identification of functional groups that could be introduced onto scaffolds to facilitate optimal binding, which allowed for increased binding with previously uncharacterized regions. MD simulations were used to elucidate primary changes that occur in the Hsp90 C-terminal binding pocket in the presence of first-generation ligands. This data was then used to design ligands that adapt to these receptor conformations, which provides access to an energy landscape that is not visible in a static model. The newly synthesized compounds demonstrated anti-proliferative activity at ~150 nanomolar concentration. The method identified herein may be used to design chemical probes that provide additional information on structural variations of Hsp90 C-terminal binding site.en_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Information and Modeling, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ci4005767.en_US
dc.subjectDrug-Designen_US
dc.subjectFlexibilityen_US
dc.subjectAllosteryen_US
dc.subjectMD simulationsen_US
dc.subjectDynamics-Based Designen_US
dc.subjectHsp90en_US
dc.titleExploiting conformational dynamics in drug discovery: design of C-terminal inhibitors of Hsp90 with improved activitiesen_US
dc.typeArticleen_US
kusw.kuauthorZhao, Huiping
kusw.kuauthorBlagg, Brian S. J.
kusw.kudepartmentMedicinal Chemistryen_US
dc.identifier.doi10.1021/ci4005767en_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmid10.1021/ci4005767.en_US
dc.rights.accessrightsopenAccess


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