14-02-2013, 09:49 AM
Molecular Docking Study of Anticancer Drugs with HDAC
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Abstract
Histone Deacetylase (HDAC) is especially known to play an important role in carcinogenesis. The enzyme has been considered a target molecule for cancer therapy, as it can induce growth arrest, differentiation, apoptosis, and autophagocytic cell death of cancer cells. Over expression of HDACs has been noted in many forms of cancers including leukemia and breast cancer. HDAC inhibitors have been shown to be potent inducers of growth arrest, differentiation, and/or apoptotic cell death. There is a growing interest in the development of histone deacetylase inhibitors as anti cancer agents. The aim of this work is to compare the HDAC‐i enzyme inhibitor based on their binding energy calculations using molecular docking.
Introduction
Cancer is a generic term for a group of over 100 chronic diseases, which can affect any part of the body. A defining feature of cancer is the rapid creation of abnormal cells, which grow beyond their usual boundary and can invade adjoining parts of the body. The cells may also spread to other organs, a process referred to as metastasis. It is expected that the Cancer incidence would have a steady increase to 15 million new cases in the year 2020 [1].
For a number of years now, a number of potential approaches have been proposed for the treatment of cancer. One of the recent targets is Histone Deacetylase (HDAC). The members of the classical HDAC family fall into two different phylogenetic classes, namely class I and class II [2]. Deacetylation is a process that removes acetyl group from the Histone tails, causing the Histone to wrap more tightly around the DNA and interfering with the transcription of genes by blocking access by transcription factors. The overall result of Deacetylation is a non‐specific reduction in the gene expression.
Methodology
All computational studies were carried on
a single machine running on a 2.16 GHz
Intel core2 duo processor with 2GB RAM
and 250 GB hard disk with Windows 7 as
an operating System.
The X-ray crystallographic structure of
Human HDAC-8 complexed with Suberoyl
Anilide Hydroxamic Acid (SAHA) was
retrieved from Protein Data Bank (PDB ID:
1T69). This structure was saved as a
standard PDB file. The saved PDB file was
viewed using SWISS-PDB Viewer
(SPDV_4.01). The Histone Deacetylase
Inhibitor (HDACi) structures were drawn
using the ACD Chemsketch12.0 [6]. About
5 known HDACi were taken into account
for the study.
Discussion
The anticancer drugs which show inhibition to HDAC that are under preclinical trials at present are generally composed of derivatives and analogs of compounds such as hydroxamic acid derivatives, benzamide derivatives, cyclic tetrapeptides and short chain fatty acids [10]. Five such compounds were chosen and docked with HDAC-8. Among the five chosen ligands, Pyroxamide has shown the highest binding energy which is much more as compared to Suberoyl Anilide Hydroxamic Acid (SAHA) although SAHA is used in majority of present anticancer drugs. The lower energy value of Pyroxamide than SAHA may be because of presence of aromatic N in Pyroxamide which can contribute to the formation of intermolecular hydrogen bonding with HDAC-8.
Conclusion
The Protein-Ligand interaction plays a
significant role in structural based drug
designing. In the present work we have
taken the receptor Histone Deacetylase
HDAC-8 and performed molecular docking
with known chemical compounds which are
under clinical trials as anticancer agents.
This analysis involves a comparative
investigation by the ranking of the
inhibitors based on their binding energy to
the HDAC-8 receptor molecule given by
their E value. In this study, compound
Pyroxamide showed maximum binding
affinity to HDAC-8 and hence can be used
as a prospective drug substance.