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Exploiting conformational dynamics in drug discovery: design of C-terminal inhibitors of Hsp90 with improved activities
Moroni, Elisabetta Zhao, Huiping Blagg, Brian S. J. Colombo, Giorgio
Moroni, Elisabetta
Zhao, Huiping
Blagg, Brian S. J.
Colombo, Giorgio
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Abstract
The 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.
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Date
2014-01-27
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American Chemical Society
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Keywords
Drug-Design, Flexibility, Allostery, MD simulations, Dynamics-Based Design, Hsp90
Citation
Moroni, 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/ci4005767