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

Balakrishnan Vijayakumar,Devadasan Velmurugan,Appavoo Umamaheswari,Ayarivan Puratchikody

doi:10.6026/97320630007134

Abstract

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.

Highlights

Histones are small basic proteins with two domains
In this study, 120 hydroxamic acid derivative inhibitors designed using Structure Based Drug Design (SBDD) approach were screened and eight compounds were taken against HDAC8 for the docking studies
These results were compared with Suberoylanilide hydroxamic acid (SAHA) using docking studies, hydrogen bond and hydrophobic interactions, binding free energy and physicochemical properties of ADME/Tox

Summary

Introduction

Histones are small basic proteins with two domains. The Cterminal domain is located inside the nucleosome core and the N-terminal domain is rich in lysine residues extending out of the nucleosome core [1]. Positive charge of the lysine residues makes the histones to bind with the negatively charged DNA that mainly regulates the interactions between DNA and histones. Among the above four histones, H3 and H4 are mainly targeted for various posttranslational modifications including acetylation, phosphorylation, and methylation [1, 2]. Among such modifications, in particular, acetylation has been highlighted as an important mechanism in post-transcriptional determination [2, 3]. Class I includes HDACs 1-3 and 8 that are homologous to yeast Rpd (exclusively expressed in the nucleus). Class II includes HDACs 4-7, 9 and 10 that are homologous to yeast Hda (shuttled between the cytoplasm and the nucleus). Class III includes Sirtuins 1-7 that are ISSN 0973-2063 (online) 0973-8894 (print)

Methods

Findings

Discussion

Conclusion