title: Structure-based design of 7-carbamate analogs of geldanamycin.
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.
authors.affiliation: Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, CA 94545, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Rastelli
authors.forename: Zong-Qiang
authors.initials: ZQ
authors.lastname: Tian
authors.forename: Zhan
authors.initials: Z
authors.lastname: Wang
authors.forename: David
authors.initials: D
authors.lastname: Myles
authors.forename: Yaoquan
authors.initials: Y
authors.lastname: Liu
mesh_terms: D016227:Benzoquinones; D001665:Binding Sites; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D047029:Lactams, Macrocyclic; D008024:Ligands; D015394:Molecular Structure; D011809:Quinones / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D016227:Benzoquinones; D002219:Carbamates; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008024:Ligands; D011809:Quinones; C001277:geldanamycin