Kokkonen Piia, Kokkola Tarja, Suuronen Tiina, Poso Antti, Jarho Elina, Lahtela-Kakkonen Maija
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
Eur J Pharm Sci. 2015 Aug 30;76:27-32. doi: 10.1016/j.ejps.2015.04.025. Epub 2015 May 1.
Sirtuins (SIRT1-SIRT7) are NAD dependent deacetylases and intriguing drug targets in for example neurodegenerative diseases and cancer. Virtual screening has been shown to be a fast and efficient method of discovering new sirtuin inhibitors. In this study, a new putative binding site on the zinc binding domain of sirtuins was utilized to screen the ZINC database virtually in order to discover new sirtuin inhibiting scaffolds. Altogether 26 compounds were tested in vitro and initially 15 inhibitors displayed >30% SIRT3 inhibition. However, the evaluation of raw data from in vitro assay revealed that many of the compounds had intrinsic property to interfere with the fluorescence signal at the assay wavelengths resulting in false positives. All compounds with over 30% SIRT3 inhibition were studied more closely for their behavior in the assay and eventually, three compounds were identified as novel sirtuin inhibitors. They displayed 32-40% SIRT3 and 21-60% SIRT2 inhibition. The inhibitors display two new scaffolds, the smaller of which can be considered as a promising fragment, which offers a base for structural optimization.
沉默调节蛋白（SIRT1 - SIRT7）是依赖烟酰胺腺嘌呤二核苷酸（NAD）的脱乙酰酶，是神经退行性疾病和癌症等领域极具吸引力的药物靶点。虚拟筛选已被证明是发现新型沉默调节蛋白抑制剂的一种快速且高效的方法。在本研究中，利用沉默调节蛋白锌结合结构域上一个新的假定结合位点对ZINC数据库进行虚拟筛选，以发现新型沉默调节蛋白抑制骨架。总共26种化合物进行了体外测试，最初有15种抑制剂对SIRT3的抑制率>30%。然而，对体外实验原始数据的评估表明，许多化合物具有在实验波长下干扰荧光信号的固有特性，从而导致假阳性结果。对所有SIRT3抑制率超过30%的化合物在实验中的行为进行了更深入的研究，最终确定了三种化合物为新型沉默调节蛋白抑制剂。它们对SIRT3的抑制率为32 - 40%，对SIRT2的抑制率为21 - 60%。这些抑制剂展示了两种新的骨架，其中较小的一种可被视为一个有前景的片段，为结构优化提供了基础。
