Binding free energy calculations and biological testing of novel thiobarbiturates as inhibitors of the human NAD+ dependent histone deacetylase Sirt2

A multi-step virtual screening was carried out in order to identify inhibitors of human NAD(+)- dependent deacetylase sirtuin 2 (Sirt2). Molecular mechanics Poisson-Boltzmann surface area (MM-PB/SA) and linear interaction energy (LIE) calculations were carried out on a training set of ten recently identified Sirt2 inhibitors from our laboratory. The docking scores did not reproduce the relative binding free energies estimated from the in vitro data, while the LIE and the MM-PB/SA data were found to be in good agreement with the experimental data for the ten inhibitors. Both binding free energy methods were successful in predicting the activity of 14 novel identified thiobarbiturates and led to Sirt2 inhibitors that are ten-fold more active than those from the training set. The provided data obtained by the combination of docking and MD-based binding free energy calculations show the performance of the approach for predicting the binding free energy of novel sirtuin inhibitors.