Document Detail

An in silico approach to discovering novel inhibitors of human sirtuin type 2.
MedLine Citation:
PMID:  15566299     Owner:  NLM     Status:  MEDLINE    
Type 2 human sirtuin (SIRT2) is a NAD(+)-dependent cytoplasmic protein that is colocalized with HDAC6 on microtubules. SIRT2 has been shown to deacetylate alpha-tubulin and to control mitotic exit in the cell cycle. To date, some small molecular inhibitors of SIRT2 have been identified; however, more inhibitors are still needed to improve the understanding of SIRT2 biological function and to discover its possible therapeutic indications. In this paper, an in silico identification procedure is described for discovering novel SIRT2 inhibitors. Molecular modeling and virtual screening were utilized to find potential compounds, which were then subjected to experimental tests for their SIRT2 inhibitory activity. Five of the 15 compounds tested in vitro showed inhibitory activity toward SIRT2, yielding a hit ratio of 33% in a micromolar level and thus demonstrating the usefulness of this procedure in finding new bioactive compounds. Two of the five compounds yielded in vitro IC(50) values of 56.7 and 74.3 microM, and these can be considered as novel inhibitors of SIRT2. On the basis of our results, a phenol moiety on the active compound is suggested to be important for SIRT2 inhibitory activity. This phenol group, together with a hydrophobic moiety and hydrogen-bonding features, is suggested to form an active SIRT2 pharmacophore.
Anu J Tervo; Sergiy Kyrylenko; Päivi Niskanen; Antero Salminen; Jukka Leppänen; Tommi H Nyrönen; Tomi Järvinen; Antti Poso
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  47     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-11-29     Completed Date:  2005-01-06     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6292-8     Citation Subset:  IM    
Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, 70211 Kuopio, Finland.
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MeSH Terms
Anthraquinones / chemistry
Benzene Derivatives / chemistry
Binding Sites
Crystallography, X-Ray
Databases, Factual
Models, Molecular
Molecular Structure
Phenols / chemistry
Pyridines / chemistry
Sirtuin 2
Sirtuins / antagonists & inhibitors*,  chemistry*
Triazoles / chemistry
Reg. No./Substance:
0/Anthraquinones; 0/Benzene Derivatives; 0/Phenols; 0/Pyridines; 0/Triazoles; EC 3.5.1.-/SIRT2 protein, human; EC 3.5.1.-/Sirtuin 2; EC 3.5.1.-/Sirtuins

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