Identification of HDAC6 selective inhibitors: pharmacophore based virtual screening, molecular docking and molecular dynamics simulation

HDAC6 regulates the expression and activity of various tumor-related proteins, but currently there is no selective inhibitor targeting HDAC6 for clinical application. In order to discover novel HDAC6 inhibitors, virtual screening methods comprised of pharmacophore based virtual screening, molecular docking and molecular dynamics (MD) simulations were employed. 15 molecules were obtained after virtual screening. After in vitro bioassays, two of the hits showed inhibition activity against HDAC6, among which the inhibition activity of G1 to HDAC6 reached 81% at concentration of 20 μM. In addition, the inhibitory activity against HDAC1 and HDAC10 demonstrated that G1 and G10 were highly selective to HDAC6. The analysis of the binding modes of G1 and G10 provides a reference for further development of highly active HDAC6 inhibitors. Communicated by Ramaswamy H. Sarma.