title: Structure-activity relationship and interaction studies of new SIRT1 inhibitors with the scaffold of 3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole.
abstract: SIRT1 is a NAD(+)-dependent deacetylase. It deacetylates a broad range of substrates and is involved in multiple diseases such as type 2 diabetes and cancer. Here we discovered a new class of SIRT1 inhibitors with the scaffold of 3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole. The inhibitors up-regulate acetyl p53 level in human breast cells MCF-7. The docking simulations indicated that the scaffold and the R-substituents of the inhibitors bind in the C and D pocket of SIRT1, respectively, which was supported by the structure-activity relationship and SIRT1 mutagenesis studies. We propose that binding of the inhibitors repels the entering of the nicotinamide moiety of NAD(+) to the C pocket, prevents its transformation to the productive conformation and therefore inhibits the deacetylation catalyzed by SIRT1.
authors.affiliation: Department of Pharmacology III, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, China.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Wu
authors.affiliation: School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Jianneng
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, China.
authors.forename: Ming-Hua
authors.initials: MH
authors.lastname: Xu
authors.affiliation: Department of Pharmacology III, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, China. Electronic address: dxl@mail.shcnc.ac.cn.
authors.forename: Dongxiang
authors.initials: D
authors.lastname: Liu
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D013830:Thiadiazoles; D014230:Triazoles; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: 3-(Furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives; Deacetylation; Inhibitor; Protein–ligand interaction; SIRT1; Structure–activity relationship