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J Chem Theory Comput. 2010 Sep 14;6(9):2978-89. doi: 10.1021/ct100334n. Epub 2010 Aug 30.

Dynamics-Based Discovery of Allosteric Inhibitors: Selection of New Ligands for the C-terminal Domain of Hsp90.

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Istituto di Chimica del Riconoscimento Molecolare, CNR, Via Mario Bianco 9, 20131 Milano, Italy, Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, and Department of Pharmaceutical Chemistry, School of Pharmacy and Center for Bioinformatics, University of Kansas, Lawrence, Kansas 66047.


The study of allosteric functional modulation in dynamic proteins is attracting increasing attention. In particular, the discovery of new allosteric sites may generate novel opportunities and strategies for drug development, overcoming the limits of classical active-site oriented drug design. In this paper, we report on the results of a novel, ab initio, fully computational approach for the discovery of allosteric inhibitors based on the physical characterization of signal propagation mechanisms in proteins and apply it to the important molecular chaperone Hsp90. We first characterize the allosteric "hot spots" involved in interdomain communication pathways from the nucleotide-binding site in the N-domain to the distal C-domain. On this basis, we develop dynamic pharmacophore models to screen drug libraries in the search for small molecules with the functional and conformational properties necessary to bind these "hot spot" allosteric sites. Experimental tests show that the selected moelcules bind the Hsp90 C-domain, exhibit antiproliferative activity in different tumor cell lines, while not affecting proliferation of normal human cells, destabilize Hsp90 client proteins, and disrupt association with several cochaperones known to bind the N- and M-domains of Hsp90. These results prove that the hits alter Hsp90 function by affecting its conformational dynamics and recognition properties through an allosteric mechanism. These findings provide us with new insights on the discovery and development of new allosteric inhibitors that are active on important cellular pathways through computational biology. Though based on the specific case of Hsp90, our approach is general and can readily be extended to other target proteins and pathways.


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