Uciechowska Urszula, Schemies Jörg, Neugebauer Robert C, Huda Elisabeth-Maria, Schmitt Martin L, Meier Rene, Verdin Eric, Jung Manfred, Sippl Wolfgang
Martin-Luther Universität Halle-Wittenberg, Department of Pharmaceutical Chemistry, Wolfgang-Langenbeckstr. 4, 06120 Halle/Saale, Germany.
ChemMedChem. 2008 Dec;3(12):1965-76. doi: 10.1002/cmdc.200800104.
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.
烟酰胺腺嘌呤二核苷酸（NAD⁺）依赖性组蛋白去乙酰化酶（沉默调节蛋白）是一类能够从组蛋白和其他蛋白质的赖氨酸残基上切割乙酰基的酶。强效选择性沉默调节蛋白抑制剂是研究这些酶生物学功能的有趣工具，并且可能成为未来治疗癌症或神经退行性疾病的药物。在此，我们展示了对一个商业数据库进行基于蛋白质的虚拟筛选以及随后对最有前景的化合物进行生物学测试的结果。对接和体外实验测试相结合，鉴定出了具有硫代巴比妥酸盐结构的新型沉默调节蛋白抑制剂。为了合理解释实验结果，通过分子力学泊松 - 玻尔兹曼/表面积（MM - PBSA）计算进行了自由能计算。观察到计算出的结合自由能与测量的Sirt2抑制活性之间存在显著相关性。分析揭示了所鉴定的硫代巴比妥酸盐衍生物与人Sirt2相互作用的分子基础。基于对接和MM - PBSA计算，我们又合成并测试了另外五种硫代巴比妥酸盐。MM - PBSA方法正确预测了新型硫代巴比妥酸盐的活性。所鉴定的化合物将用于进一步探索沉默调节蛋白抑制剂的治疗潜力。
