Tervo Anu J, Kyrylenko Sergiy, Niskanen Päivi, Salminen Antero, Leppänen Jukka, Nyrönen Tommi H, Järvinen Tomi, Poso Antti
Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, 70211 Kuopio, Finland.
J Med Chem. 2004 Dec 2;47(25):6292-8. doi: 10.1021/jm049933m.
Type 2 human sirtuin (SIRT2) is a NAD(+)-dependent cytoplasmic protein that is colocalized with HDAC6 on microtubules. SIRT2 has been shown to deacetylate alpha-tubulin and to control mitotic exit in the cell cycle. To date, some small molecular inhibitors of SIRT2 have been identified; however, more inhibitors are still needed to improve the understanding of SIRT2 biological function and to discover its possible therapeutic indications. In this paper, an in silico identification procedure is described for discovering novel SIRT2 inhibitors. Molecular modeling and virtual screening were utilized to find potential compounds, which were then subjected to experimental tests for their SIRT2 inhibitory activity. Five of the 15 compounds tested in vitro showed inhibitory activity toward SIRT2, yielding a hit ratio of 33% in a micromolar level and thus demonstrating the usefulness of this procedure in finding new bioactive compounds. Two of the five compounds yielded in vitro IC(50) values of 56.7 and 74.3 microM, and these can be considered as novel inhibitors of SIRT2. On the basis of our results, a phenol 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, is suggested to form an active SIRT2 pharmacophore.
2型人沉默调节蛋白（SIRT2）是一种依赖烟酰胺腺嘌呤二核苷酸（NAD(+)）的胞质蛋白，它与组蛋白去乙酰化酶6（HDAC6）在微管上共定位。已证明SIRT2可使α-微管蛋白去乙酰化，并控制细胞周期中的有丝分裂退出。迄今为止，已鉴定出一些SIRT2的小分子抑制剂；然而，仍需要更多抑制剂来增进对SIRT2生物学功能的理解，并发现其可能的治疗适应症。本文描述了一种用于发现新型SIRT2抑制剂的计算机识别程序。利用分子建模和虚拟筛选来寻找潜在化合物，然后对其SIRT2抑制活性进行实验测试。在体外测试的15种化合物中有5种对SIRT2表现出抑制活性，在微摩尔水平上的命中率为33%，从而证明了该程序在寻找新的生物活性化合物方面的有效性。这5种化合物中的2种在体外的半数抑制浓度（IC(50)）值分别为56.7和74.3微摩尔，这些可被视为SIRT2的新型抑制剂。根据我们的结果，活性化合物上的酚基部分对SIRT2抑制活性很重要。该酚基与疏水部分和氢键特征一起，被认为形成了一个活性SIRT2药效团。
