Structural and quantum chemical studies of 8-aryl-sulfanyl adenine class Hsp90 inhibitors Journal Article
| Authors: | Immormino, R. M.; Kang, Y.; Chiosis, G.; Gewirth, D. T. |
| Article Title: | Structural and quantum chemical studies of 8-aryl-sulfanyl adenine class Hsp90 inhibitors |
| Abstract: | Hsp90 chaperones play a critical role in modulating the activity of many cell signaling proteins and are an attractive target for anti-cancer therapeutics. We report here the structures of the water soluble 8-aryl-sulfanyl adenine class Hsp90 inhibitors, 1 (PU-H71) and 2 (PU-H64), in complex with the N-terminal domain of human Hsp90α. The conformation of 1 when bound to Hsp90 differs from previously reported 8-aryl adenine Hsp90 inhibitors including 3 (PU24FCl). While the binding mode for 3 places the 2′-halide of the 8-aryl group on top of the adenine ring, for 1 and 2, we show that the 2′-halide is rotated approximately 180° away. This difference explains the opposing trends in Hsp90 inhibitory activity for the 2′-halo derivatives of the 3′,4′,5′-trimethoxy series where Cl > Br > I compared to the 4′,5′-methylenedioxy series where I > Br > Cl. We also present quantum chemical calculations of 2 and its analogues that illuminate their basis for Hsp90 inhibition. The calculated conformation of 2 agreed well with the crystallographically observed conformations of 1 and 2. The predictive nature of the calculations has allowed the exploration of additional derivatives based on the 8-aryl adenine scaffold. © 2006 American Chemical Society. |
| Keywords: | signal transduction; antineoplastic agents; antineoplastic agent; protein domain; complex formation; structure activity relation; amino terminal sequence; heat shock protein 90 inhibitor; pu h71; heat shock protein 90; hsp90 heat-shock proteins; hydrogen bond; models, molecular; solutions; crystallography, x-ray; binding sites; crystallization; drug binding site; ic 50; x ray crystallography; ligand binding; stereospecificity; molecular conformation; drug protein binding; oxidation-reduction; polycyclic aromatic hydrocarbon derivative; calculation; adenine; iodine; chaperone; quantum theory; quantum chemistry; drug conformation; chlorine; halide; adenine derivative; bromine; pu h64; sulfanilic acids |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 49 |
| Issue: | 16 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 2006-08-10 |
| Start Page: | 4953 |
| End Page: | 4960 |
| Language: | English |
| DOI: | 10.1021/jm060297x |
| PUBMED: | 16884307 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 26" - "Export Date: 4 June 2012" - "CODEN: JMCMA" - "Source: Scopus" |
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