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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\u2010based virtual screen of a commercial database with subsequent biological testing of the most promising compounds. The combination of docking and in\u2005vitro experimental testing resulted in the identification of novel sirtuin inhibitors with thiobarbiturate structure. To rationalize the experimental results, free\u2010energy calculations were carried out by molecular mechanics Poisson\u2013Boltzmann\/surface area (MM\u2010PBSA) 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\u2010PBSA calculations we synthesized and tested five further thiobarbiturates. The MM\u2010PBSA method correctly predicted the activity of the novel thiobarbiturates. The identified compounds will be used to further explore the therapeutic potential of sirtuin inhibitors.<\/jats:p>","DOI":"10.1002\/cmdc.200800104","type":"journal-article","created":{"date-parts":[[2008,11,5]],"date-time":"2008-11-05T09:51:05Z","timestamp":1225878665000},"page":"1965-1976","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Thiobarbiturates as Sirtuin Inhibitors: Virtual Screening, Free\u2010Energy Calculations, and Biological 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