title: Quantitative insights for the design of substrate-based SIRT1 inhibitors.
abstract: Sirtuin 1 (SIRT1) is the most studied human sirtuin and it catalyzes the deacetylation reaction of acetylated lysine residues of its target proteins, for example histones. It is a promising drug target in the treatment of age-related diseases, such as neurodegenerative diseases and cancer. In this study, a series of known substrate-based sirtuin inhibitors was analyzed with comparative molecular field analysis (CoMFA), which is a three-dimensional quantitative structure-activity relationships (3D-QSAR) technique. The CoMFA model was validated both internally and externally, producing the statistical values concordance correlation coefficient (CCC) of 0.88, the mean value r(2)m of 0.66 and Q(2)F3 of 0.89. Based on the CoMFA interaction contours, 13 new potential inhibitors with high predicted activity were designed, and the activities were verified by in vitro measurements. This work proposes an effective approach for the design and activity prediction of new potential substrate-based SIRT1 inhibitors.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Piia
authors.initials: P
authors.lastname: Kokkonen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mellini
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Nyrhilä
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Rahnasto-Rilla
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Suuronen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Kiviranta
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Tero
authors.initials: T
authors.lastname: Huhtiniemi
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. Electronic address: Elina.Jarho@uef.fi.
authors.forename: Elina
authors.initials: E
authors.lastname: Jarho
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. Electronic address: Maija.Lahtela-Kakkonen@uef.fi.
authors.forename: Maija
authors.initials: M
authors.lastname: Lahtela-Kakkonen
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: CoMFA; Inhibitor; QSAR; SIRT1; Sirtuin