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ID: ALA1143641

Journal: Bioorg Med Chem Lett

Title: Structure-based design of 7-carbamate analogs of geldanamycin.

Authors: Rastelli G, Tian ZQ, Wang Z, Myles D, Liu Y.

Abstract: The 7-carbamate groups of geldanamycin and its 17-(2-dimethylaminoethyl)amino-17-demethoxy derivative (17-DMAG) bind the N-terminal domain of Hsp90 by establishing a network of hydrogen bonds which involve four buried water molecules. In this study, a structure-based approach was used to investigate the effects of displacing some of these waters by modification of the 7-carbamate. A general loss of binding to human Hsp90 was observed, except for replacement of the carbamate with a hydroxamate group which gave an analog with weak activity. Modeling of Hsp90-ligand interactions suggested that the hydroxamate was not able to displace the buried water molecules, while bulkier substituents able to do so proved inactive.

CiteXplore: 16165354

DOI: 10.1016/j.bmcl.2005.08.013