Quantitative insights for the design of substrate-based SIRT1 inhibitors.

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.

Peptides and Pseudopeptides as SIRT6 Deacetylation Inhibitors.

SIRT6 belongs to the family of histone deacetylases (class III), but it also has mono-ADP-ribosyltransferase activity. SIRT6 is a nuclear sirtuin that has been associated with aging, cellular protection, and sugar metabolism. Despite these important roles for SIRT6, thus far, there are only a few weak SIRT6 inhibitors available, and no structure-activity relationship (SAR) studies have been published. This is the first study concerning peptides and pseudopeptides as SIRT6 deacetylation inhibitors and the first SAR data concerning SIRT6. We also investigated the molecular interactions using a homology model. We report three compounds exhibiting 62-91% SIRT6 inhibition at 200 µM concentration. These compounds can serve as starting points for systematic SAR studies and SIRT6 inhibitor design.

N(epsilon)-thioacetyl-lysine-containing tri-, tetra-, and pentapeptides as SIRT1 and SIRT2 inhibitors.

N()-Thioacetyl-lysine-containing tri-, tetra-, and pentapeptides, based on the alpha-tubulin and p53 protein sequences, were studied as SIRT1 and SIRT2 inhibitors. The potency of the pentapeptides depended on the selection of the side chains. The removal of N- and C-terminal residues of the pentapeptides yielded tripeptides with retained SIRT1 inhibitory activity but decreased SIRT2 inhibitory activity. The most potent SIRT1 inhibitors were equipotent with the reference compound (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) with the IC(50) values of 180-330 nM.

Characterization of the binding properties of SIRT2 inhibitors with a N-(3-phenylpropenoyl)-glycine tryptamide backbone.

SIRT2 inhibitors with a N-(3-phenylpropenoyl)-glycine tryptamide backbone were studied. This backbone has been developed in our group, and it is derived from a compound originally found by virtual screening. In addition, compounds with a smaller 3-phenylpropenoic acid tryptamide backbone were also included in the study. Binding modes for the new compounds and the previously reported compounds were analyzed with molecular modelling methods. The approach, which included a combination of molecular dynamics, molecular docking and cluster analysis, showed that certain docking poses were favourable despite the conformational variation in the target protein. The N-(3-phenylpropenoyl)-glycine tryptamide backbone is also a good backbone for SIRT2 inhibitors, and the series of compounds includes several potent SIRT2 inhibitors.

N-(3-(4-Hydroxyphenyl)-propenoyl)-amino acid tryptamides as SIRT2 inhibitors.

A series of N-(3-(4-hydroxyphenyl)-propenoyl)-amino acid tryptamides was based on a previously reported new SIRT2 inhibitor from our group, and it was designed to study if the molecular size of the compound could be reduced. The most potent compounds, N-(3-(4-hydroxyphenyl)-propenoyl)-2-aminoisobutyric acid tryptamide and N-(3-(4-hydroxyphenyl)-propenoyl)-L-alanine tryptamide, were equipotent, 30% smaller in molecular weight, and slightly more selective (SIRT2/SIRT1) than the parent compound.

N,N'-Bisbenzylidenebenzene-1,4-diamines and N,N'-Bisbenzylidenenaphthalene-1,4-diamines as Sirtuin Type 2 (SIRT2) Inhibitors.

A series of N,N'-bisbenzylidenebenzene-1,4-diamine and N,N'-bisbenzylidenenaphthalene-1,4-diamine derivatives were synthesized as inhibitors for human sirtuin type 2 (SIRT2). The design of the new compounds was based on two earlier reported hits from molecular modeling and virtual screening. The most potent compound was N,N'-bis(2-hydroxybenzylidene)benzene-1,4-diamine, which was equipotent with the most potent hit compound and well-known SIRT2 inhibitor sirtinol.

Discovering inhibitors of human sirtuin type 2: novel structural scaffolds.

A successful virtual screening experiment of novel SIRT2 inhibitors is described. Four out of 11 experimentally tested compounds showed in vitro inhibitory activity toward SIRT2 in a micromolar level, resulting in an experimental hit ratio of 36%. Two of these compounds inhibited SIRT2 with IC50 (microM) values of 51 and 91; moreover, one of the new inhibitors was comprised of an entirely new SIRT2-inhibiting structural scaffold.