title: Identification of novel SIRT3 inhibitor scaffolds by virtual screening.
abstract: SIRT3 is a member of the sirtuin family of histone deacetylases. It is a mitochondrial protein, which has an important role in metabolic homeostasis but it may also act as a tumor suppressor or promoter. Increased SIRT3 transcription has been associated with node-positive breast cancer and oral squamous cell carcinoma. To identify novel SIRT3 inhibitors we have established a virtual screening workflow by using shape-based filtering and flexible docking protocol. The Chembridge database was screened and 40 molecules were selected and tested in an in vitro assay. Two novel scaffolds were identified among the tested hits. The 5-amino-2-phenyl-benzoxazole scaffold was selected for further structure-activity studies and a series of its analogs was tested. The SIRT3 inhibition for this series ranged between 13% and 71%.
authors.affiliation: School of Pharmacy, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
authors.forename: Heikki S
authors.initials: HS
authors.lastname: Salo
authors.forename: Tuomo
authors.initials: T
authors.lastname: Laitinen
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.forename: Elina
authors.initials: E
authors.lastname: Jarho
authors.forename: Maija
authors.initials: M
authors.lastname: Lahtela-Kakkonen
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D056566:Sirtuin 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001583:Benzoxazoles; D004791:Enzyme Inhibitors; C525046:Sirt3 protein, mouse; C466093:SIRT3 protein, human; D056566:Sirtuin 3