SMALL MOLECULE AFFINITIES FOR SIRT-1 DEACETYLASE ENZYME

Martin Brenneman, Amy Stockert and Tarek M. Mahfouz

Department of Pharmaceutical and Biomedical Sciences Raabe, College of Pharmacy, Ohio Northern University Ada, Ohio, USA

Abstract

Cinnamon has been shown to decrease blood glucose levels in type-II diabetics. Analysis of cinnamon extract have determined that it contains a number of polyphenolic compounds and the antidiabetic effect of cinnamon is hypothesized to be due to those phenolic compounds. The protein target of those phenolic compounds has not been identified yet. However, Sirtuin-1 (Sirt-1), a deacetylase in the insulin signaling pathway, seems a likely target. To investigate this possibility, we docked several polyphenolic compounds that are commonly found in cinnamon extract to Sirt-1 in order to determine their binding affinities and compared these to Sirt-1 affinity for resveratrol which is not in cinnamon extract, but it is a known activator of Sirt-1. We used Sirt-1 structure 5BTR for the docking which contained three molecules of resveratrol with a 7-amino-4-methylcoumarin (AMC)-containing peptide in the binding site. Our results indicate a cooperative binding of resveratrol molecules when docked sequentially in the binding site with the AMC peptide. We further hypothesized that the polyphenolic compounds within cinnamon would have a similar effect. To investigate this, a second set of docking simulations was performed on the polyphenolic compounds within cinnamon extract to investigate potentially similar interactions as shown by resveratrol. These docking simulations were done using AutoDock Vina in two different trials; one using sets of three of the same molecule, and the second using sets of combinations of three molecules. Results from those trials showed similar and sometimes stronger interactions than resveratrol between Sirt-1 and the molecules docked. Molecules with affinities at least as strong as resveratrol’s were used for sequential docking runs. These results strongly suggest that Sirt-1 is a possible target for cinnamon extract.