Linked Life Data

18985648

Source:http://linkedlifedata.com/resource/pubmed/id/18985648

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2008-12-22
pubmed:abstractText
NAD+-dependent histone deacetylases (sirtuins) are enzymes that cleave acetyl groups from lysine residues in histones and other proteins. Potent selective sirtuin inhibitors are interesting tools for the investigation of the biological functions of these enzymes and may be future drugs for the treatment of cancer or neurodegenerative diseases. Herein we present the results from a protein-based virtual screen of a commercial database with subsequent biological testing of the most promising compounds. The combination of docking and in vitro experimental testing resulted in the identification of novel sirtuin inhibitors with thiobarbiturate structure. To rationalize the experimental results, free-energy calculations were carried out by molecular mechanics Poisson-Boltzmann/surface area (MM-PBSA) calculations. A significant correlation between calculated binding free energies and measured Sirt2 inhibitory activities was observed. The analyses suggested a molecular basis for the interaction of the identified thiobarbiturate derivatives with human Sirt2. Based on the docking and MM-PBSA calculations we synthesized and tested five further thiobarbiturates. The MM-PBSA method correctly predicted the activity of the novel thiobarbiturates. The identified compounds will be used to further explore the therapeutic potential of sirtuin inhibitors.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1860-7187
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
3
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1965-76
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Thiobarbiturates as sirtuin inhibitors: virtual screening, free-energy calculations, and biological testing.
pubmed:affiliation
Martin-Luther Universität Halle-Wittenberg, Department of Pharmaceutical Chemistry, Wolfgang-Langenbeckstr. 4, 06120 Halle/Saale, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't