Selection of an improved HDAC8 inhibitor through structure-based drug design

Histone deacetylases (HDACs) are enzymes, which catalyze the removal of acetyl moiety from acetyl-lysine within the histone proteins and promote gene repression and silencing resulting in several types of cancer. HDACs are important therapeutic targets for the treatment of cancer and related diseases. Hydroxamic acid inhibitors show promising results in clinical trials against carcinogenesis. 120 hydroxamic acid derivatives were designed as inhibitors based on hydrophobic pocket and the Zn (II) catalytic site of HDAC8 active site using Structure Based Drug Design (SBDD) approach. High Throughput Virtual screening (HTVs) was used to filter the effective inhibitors. Induced Fit Docking (IFD) studies were carried out for the screening of eight inhibitors using Glide software. Hydrogen bond, hydrophobic interactions and octahedral coordination geometry with Zn (II) were observed in the IFD complexes. Prime MM-GBSA calculation was carried out for the binding free energy, to observe the stability of docked complexes. The Lipinski's rule of five was analyzed for ADME/Tox drug likeliness using Qikprop simulation. These inhibitors have good inhibitory properties as they have favorable docking score, energy, emodel, hydrogen bond and hydrophobic interactions, binding free energy and ADME/Tox. However, one compound (Cmp22) successively satisfied all the studies among the eight compounds screened and seems to be a promising potent inhibitor against HDAC8.