Molecular Simulation of HDAC1/3 Inhibitor: Insights into the Structural Basis of Selectivity

A group of class I selective HDAC inhibitors were derived previously, with inhibitory preference of HDAC1 and HDAC3 over HDAC2. Molecular docking and molecular dynamic simulation approaches were performed to elucidate the structural basis of inhibitor’s selectivity between HDAC2 and HDAC3. Superimposition of the rigid docked structures showed that residues in the active sites of both receptors are identical, and the inhibitor (D18) has similar binding patterns in both sites. Results of the flexible docking suggested that strong hydrophobic interactions between molecule D18 and Phe199 play significant role in the selectivity. The interactions were verified to be stable by further molecular dynamic simulation processes.