| Abstract
| - Type 2 human sirtuin (SIRT2) is a NAD+-dependent cytoplasmic protein that is colocalizedwith HDAC6 on microtubules. SIRT2 has been shown to deacetylate α-tubulin and to controlmitotic exit in the cell cycle. To date, some small molecular inhibitors of SIRT2 have beenidentified; however, more inhibitors are still needed to improve the understanding of SIRT2biological function and to discover its possible therapeutic indications. In this paper, an insilico identification procedure is described for discovering novel SIRT2 inhibitors. Molecularmodeling and virtual screening were utilized to find potential compounds, which were thensubjected to experimental tests for their SIRT2 inhibitory activity. Five of the 15 compoundstested in vitro showed inhibitory activity toward SIRT2, yielding a hit ratio of 33% in amicromolar level and thus demonstrating the usefulness of this procedure in finding newbioactive compounds. Two of the five compounds yielded in vitro IC50 values of 56.7 and 74.3μM, and these can be considered as novel inhibitors of SIRT2. On the basis of our results, aphenol moiety on the active compound is suggested to be important for SIRT2 inhibitory activity.This phenol group, together with a hydrophobic moiety and hydrogen-bonding features, issuggested to form an active SIRT2 pharmacophore.
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