Discovery of New SIRT2 Inhibitors by Utilizing a Consensus Docking/Scoring Strategy and Structure-Activity Relationship Analysis
SIRT2,which is a NAD+(nicotinamide adenine dinucleotide)dependent deacetylase,has been demonstrated to play an important role in the occurrence and development of a variety of diseases such as cancer,ischemia-reperfusion,and neurodegenerative diseases.Small molecule inhibitors of SIRT2 are thought to be potential interfering agents for relevant diseases.Discovery of SIRT2 inhibitors has attracted much attention recently.In this investigation,we adopted a consensus docking/scoring strategy to screen for novel SIRT2 inhibitors.Structural optimization and structure-activity relationship(SAR)analysis were then carried out on highly potent compounds with new scaffolds,which led to the discovery of 2-((5-benzyl-5H-”1,2,4”triazino”5,6-b”indol-3-yl)thio)-N-(naphthalen-1-yl)acetamide(SR86).This compound showed good activity against SIRT2 with an IC50 value of 1.3 μM.SR86 did not exhibit activity against SIRT1 and SIRT3,implying a good selectivity for SIRT2.In in vitro cellular assays,SR86 displayed very good antiviability activity against breast cancer cell line MCF-7.In Western blot assays,SR86 showed considerable activity in blocking the deacetylation of α-tubulin,which is a typical substrate of SIRT2.Collectively,because of the new scaffold structure and good selectivity of SR86,it could serve as a promising lead compound,hence deserving further studies.
Shenzhen Huang Chunli Song Xiang Wang Guo Zhang Yanlin Wang Xiaojuan Jiang Qizheng Sun Luyi Huang Rong Xiang Yiguo Hu Linli Li Shengyong Yang
State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University/Collabor Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education,West China School Department of Clinical Medicine,School of Medicine,Nankai University,Tianjin 300071,China
国内会议
第九届国际分子模拟与信息技术应用学术会议(ICMS&I2018)
太原
英文
284-294
2018-05-01（万方平台首次上网日期，不代表论文的发表时间）