Investigation of silent information regulator 1 (Sirt1) agonists from Traditional Chinese Medicine.

Silent information regulator 1 (Sirt1), a class III nicotinamide adenine dinucleotide dependent histone deacetylases, is important in cardioprotection, neuroprotection, metabolic disease, calorie restriction, and diseases associated with aging. Traditional Chinese Medicine (TCM) compounds from TCM Database@Taiwan ( http://tcm.cmu.edu.tw/ ) were employed for screening potent Sirt1 agonists, and molecular dynamics (MD) simulation was implemented to simulate ligand optimum docking poses and protein structure under dynamic conditions. TCM compounds such as (S)-tryptophan-betaxanthin, 5-O-feruloylquinic acid, and RosA exhibited good binding affinity across different computational methods, and their drug-like potential were validated by MD simulation. Docking poses indicate that the carboxylic group of the three candidates generated H-bonds with residues in the protein chain from Ser441 to Lys444 and formed H-bond, π-cation interactions, or hydrophobic contacts with Phe297 and key active residue, His363. During MD, stable π-cation interactions with residues Phe273 or Arg274 were formed by (S)-tryptophan-betaxanthin and RosA. All candidates were anchored to His363 by stable π- or H-bonds. Hence, we propose (S)-tryptophan-betaxanthin, 5-O-feruloylquinic acid, and RosA as potential lead compounds that can be further tested in drug development process for diseases associated with aging An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:28.