Identification of specific and semi-specific SIRT inhibitors through computer-aided studies

+-dependent lysine deacetylases (sirtuins, SIRT1-7) have emerged as potential therapeutic targets for treatment of human illnesses such as cancer, metabolic, cardiovascular and neurodegenerative diseases. Sirtuins possess deacetylase and/or mono-ADP-ribosyltransferase activity, and this activity is directed to histone as well as non-histone targets involved in transcription, metabolism, and energy homeostasis [1,2]. SIRT1, having in cells a nuclear localization, has been widely recognized to play a multifaceted, protective role in aging, metabolism, and neurodegeneration [3]. In cancer, the role of SIRT1 is highly debated. Among SIRT1/2 inhibitors, sirtinol induced senescence-like growth arrest in human breast cancer MCF-7 cells and lung cancer H1299 cells [4] and inhibited cell growth in prostate cancer [5]; cambinol induced apoptosis in BCL6-expressing Burkitt lymphoma cells [6]; salermide was well tolerated by mice at concentrations up to 100 μM and prompted tumor-specific apoptosis in a wide range of human cancer cell lines [7]; MC2141 displayed high antiproliferative activity against Raji, DLD1, and HeLa cells [8], and tenovins, identified via a yeast genetic screen for p53 activators, decreased tumor growth in vivo as single agents at low micromolar concentrations [9]. On the other hand, in some contexts SIRT1 seems to have a protective role in cancer, in particular in colon cancer. SIRT2 is a cytoplasm enzyme mainly known as α–tubulin deacetylase, highly involved in cell cycle regulation. SIRT2 crucially regulates the functions in the mitotic checkpoint elicited by mitotic stress, as well as cell death in response to DNA damage-inducing stress [10]. In addition, SIRT2 influences adipocyte differentiation by deacetylation of FOXO proteins. Despite early evidences suggested SIRT1 as the main sirtuin target to inhibit for obtaining anticancer properties, recently SIRT2 down-regulation has been described to lead to apoptosis without cell cycle arrest in HeLa cells [11]. SIRT3-5 are mithocondrial deacetylases or ADP-ribosylases (SIRT4), and control adaptive thermogenesis (SIRT3), aging (SIRT3), insulin secretion (SIRT4), and ammonia detoxification (SIRT5) [1]. Finally, SIRT6 and SIRT7 are two nuclear and nucleolar enzymes, the first involved in the control of Editorial Comment genomic DNA stability and DNA repair as well as glucose homeostasis, the latter exerting antiapoptotic properties [1]. In this month issue of AGING, Schlicker et al. described the identification of specific and semi-specific SIRT inhibitors through virtual screening performed by docking 1990 structurally different compounds into the peptide binding pockets of crystal structures of SIRT2,-3,-5, and-6. To avoid to select compounds blocking the NAD + binding site, that is common to …