Characterization the performances of twofold resveratrol integrated compounds in binding with SIRT1 by molecular dynamics simulation and molecular mechanics/generalized Born surface area (MM/GBSA) calculation

Abstract SIRT1, namely silent information regulator 1, is a kind of NAD+ dependent deacetylase, the activators of which have potential therapeutic applications. Previous studies revealed that two resveratrol molecules (RSV1 and RSV2) bound to SIRT1, and were mainly responsible for strengthening the binding of p53-AMC peptide to SIRT1 so as to activating SIRT1. Thus, we constructed four novel RSV1-RSV2 type SIRT1 activators (i.e., RSV_m1, RSV_m2, RSV_m3 and RSV_m4) by linking the structures of RSV1 and RSV2, and further evaluated their binding affinities and dynamics properties using molecular dynamics simulations. Compared with RSV1, 2, compounds RSV_m1 and RSV_m3 not only had higher binding interaction with SIRT1, but promoted the bindings of p53-AMC peptide to SIRT1 obviously. While the other two compounds were proved to be comparable to RSV1, 2. The four RSV1-RSV2 type compounds might give some valuable clues for the rational design of more promising SIRT1 activators in the near future.