Quantitative insights for the design of substrate-based SIRT1 inhibitors

Piia Kokkonen; Paolo Mellini; Olli Nyrhilä; Minna Rahnasto-Rilla; Tiina Suuronen; Päivi Kiviranta; Tero Huhtiniemi; Antti Poso; Elina Jarho; Maija Lahtela-Kakkonen

doi:10.1016/j.ejps.2014.04.003

Quantitative insights for the design of substrate-based SIRT1 inhibitors

Eur J Pharm Sci. 2014 Aug 1:59:12-9. doi: 10.1016/j.ejps.2014.04.003. Epub 2014 Apr 18.

Affiliations

¹ School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
² School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. Electronic address: Elina.Jarho@uef.fi.
³ 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.

PMID: 24747578
DOI: 10.1016/j.ejps.2014.04.003

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.

Keywords: CoMFA; Inhibitor; QSAR; SIRT1; Sirtuin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Drug Design
Enzyme Inhibitors / chemistry
Models, Molecular*
Quantitative Structure-Activity Relationship
Sirtuin 1 / antagonists & inhibitors*

Substances

Enzyme Inhibitors
SIRT1 protein, human
Sirtuin 1