Discovery of small molecule sirt1 activator using high-throughput virtual screening, molecular dynamics simulation, molecular mechanics generalized born/surface area (MM/GBSA) calculation, and biological evaluation

Sirt1, namely silent information regulator 1, belongs to a highly conserved family of NAD+-dependent deacetylase which is involved in innumerable human disorders such as obesity, type 2 diabetes, cancer, and aging. Combined high-throughput virtual screening, molecular dynamics simulation, MM/GBSA free energy calculation, and MM/GBSA free energy decomposition analysis approaches were utilized for identification of sirt1 activators. Four compounds with diverse chemical scaffold were retrieved as hits based on docking score and clustering analysis. Our simulations indicated that compound y040-6677 had the highest binding free energies, which could form one hydrogen bond with the residue Asn226. Compound y040-6677 could tightly plug into the hydrophobic allosteric site of sirt1 via strong interaction with the residues Leu215, Thr219, Gln222, Ile223, and Asn226, which were obtained from the MM/GBSA free energy decomposition. These simulation results were consistent with the in vivo enzymatic assay, which implied that compound y040-6677 had a comparable sirt1 activation compared with the reference molecule SRT1720. We hope that compound y040-6677 might represent a promising chemical scaffold for further development of novel sirt1 activators.