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Title

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

 

Authors

Balakrishnan Vijayakumar1, Appavoo Umamaheswari2, Ayarivan Puratchikody2, Devadasan Velmurugan1, 3*

 

Affiliation

1Centre of Advanced Study in Crystallography and Biophysics, University of Madras, Guindy campus, Chennai 600 025, India; 2Department of Pharmaceutical Technology, Anna University of Technology, Tiruchirappalli 620 024, India; 3Bioinformatics Infrastructure Facility (BIF), University of Madras, Guindy campus, Chennai 600 025, India

 

Email

dvelmurugan@unom.ac.in; *Corresponding author

 

Phone

+91-44-22300122

 

Fax

+91-44-22352494

 

Article Type

Hypothesis

 

Date

Received September 08, 2011; Accepted September 14, 2011; Published 28, 2011

 

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 Lipinskiís 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.

 

Keywords

ADME/Tox, HDAC, HDACI, HTVs, IFD, Prime MM-GBSA, SBDD

 

Citation

Vijayakumar et al. Bioinformation 7(3): 134-141 (2011)
 

Edited by

P Kangueane

 

ISSN

0973-2063

 

Publisher

Biomedical Informatics

 

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.