title: Thiobarbiturates as sirtuin inhibitors: virtual screening, free-energy calculations, and biological testing.
abstract: 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.
authors.affiliation: Martin-Luther Universität Halle-Wittenberg, Department of Pharmaceutical Chemistry, Wolfgang-Langenbeckstr. 4, 06120 Halle/Saale, Germany.
authors.forename: Urszula
authors.initials: U
authors.lastname: Uciechowska
authors.forename: Jörg
authors.initials: J
authors.lastname: Schemies
authors.forename: Robert C
authors.initials: RC
authors.lastname: Neugebauer
authors.forename: Elisabeth-Maria
authors.initials: EM
authors.lastname: Huda
authors.forename: Martin L
authors.initials: ML
authors.lastname: Schmitt
authors.forename: Rene
authors.initials: R
authors.lastname: Meier
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013858:Thiobarbiturates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D013858:Thiobarbiturates; D037761:Sirtuins