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Design strategies to target crystallographic waters applied to the Hsp90 molecular chaperone.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2011 Jun 15; Vol. 21 (12), pp. 3557-62. Date of Electronic Publication: 2011 May 05. - Publication Year :
- 2011
-
Abstract
- A series of novel and potent small molecule Hsp90 inhibitors was optimized using X-ray crystal structures. These compounds bind in a deep pocket of the Hsp90 enzyme that is partially comprised by residues Asn51 and Ser52. Displacement of several water molecules observed crystallographically in this pocket using rule-based strategies led to significant improvements in inhibitor potency. An optimized inhibitor (compound 17) exhibited potent Hsp90 inhibition in ITC, biochemical, and cell-based assays (K(d)=1.3 nM, K(i)=15 nM, and cellular IC(50)=0.5 μM).<br /> (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Subjects :
- Binding Sites drug effects
Crystallography, X-Ray
Humans
Inhibitory Concentration 50
Models, Molecular
Molecular Structure
Pyrimidines chemical synthesis
Pyrimidines chemistry
Pyrimidines pharmacology
Pyrroles chemical synthesis
Pyrroles chemistry
Pyrroles pharmacology
Small Molecule Libraries pharmacology
Drug Design
HSP90 Heat-Shock Proteins antagonists & inhibitors
Small Molecule Libraries chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 21
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 21612924
- Full Text :
- https://doi.org/10.1016/j.bmcl.2011.04.130