Exploration of the binding pocket of histone deacetylases: the design of potent and isoform-selective inhibitors
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Date
2017
Authors
Yelekçi, Kemal
Journal Title
Journal ISSN
Volume Title
Publisher
Tübitak
Abstract
Histone deacetylases (HDACs) are enzymes that act on histone proteins to remove the acetyl group and thereby regulate the
chromatin state. HDACs act not only on histone protein but also nonhistone proteins that are key players in cellular processes such
as the cell cycle, signal transduction, apoptosis, and more. “Classical” HDACs have been shown to be promising targets for anticancer
drug design and development. However, the selectivity of HDAC inhibitors for HDAC isoforms remains the motivation of current
research in this field. Here, we explored Class I HDACs and HDAC6 by sequence alignment and structural superimposition, catalytic
channel extraction, and identification of critical residues involved in HDAC catalysis. Based on the general pharmacophore features
of known HDAC inhibitors, we developed a library of compounds by scaffold hopping on a fragment hit identified via structurebased virtual screening of the molecular fragment library retrieved from the Otava database. Molecular docking assay revealed five of
these compounds to have increased potency and selectivity for HDACs 1 and 2. Furthermore, their predicted absorption, distribution,
metabolism, elimination, and toxicity (ADMET) properties were consistent with those of drug-like compounds. With further modelingbased and experimental investigations, we believe that these findings may offer additional potential HDAC inhibitors with improved
selectivity
Description
Keywords
Scaffold hopping, Molecular docking, ADMET analysis, Potent and isoform-selective HDAC inhibitors, Anticancer agents
Turkish CoHE Thesis Center URL
Citation
14
WoS Q
Q3
Scopus Q
Q2
Source
Volume
41
Issue
6
Start Page
901
End Page
918