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Discovery and Dynamics Behavior of a New Isoform-Selective Histone Deacetylase 2 Inhibitor Targeting the Active-Site Internal Cavity


Paper Type 
 Contributed Paper
Title 
 Discovery and Dynamics Behavior of a New Isoform-Selective Histone Deacetylase 2 Inhibitor Targeting the Active-Site Internal Cavity
Author 
 Kulisara Kittivibul, Suriya Tateing and Nuttee Suree*
Email 
 nuttee.suree@cmu.ac.th
Abstract:

 Histone deacetylase 2 (HDAC2), a human epigenetic enzyme, has become one of the

most promising targets for anti-HIV-1 latency and viral eradication due to its specific involvement
in transcriptional suppression control at the HIV-1 long terminal repeat (LTR) regions. However,
chemotherapeutic intervention by specific targeting of HDAC2 activity using inhibitors remains a
great challenge. Most HDAC inhibitors have broad activity among HDAC isoforms, resulting in
cellular toxicity and undesirable outcomes. Herein, a structure-based drug discovery was implemented
to discover new small chemical compounds selective for HDAC2. A total 3,626 compounds retrieved
from the Selleck Chemical library were virtually screened against HDAC2 protein structure. As a
result, a small-molecule 3-aminopyrazole derivative Danusertib (ZINC06718723) was identified with
the lowest binding affinity of -10.9 kcal/mol and a favorable binding pattern. Molecular dynamics
(MD) simulations was then performed at 50 ns to investigate the intermolecular interactions within the
HDAC2- Danusertib complex, compared to the apo-HDAC, HDAC2-SAHA, and HDAC2-BRD4884
complexes. Detailed energetic estimations from the molecular mechanics Poisson–Boltzmann surface
area (MM/PBSA) of the HDAC2- Danusertib complex revealed a strong binding free energy of
-41.41 kcal/mol as well as multiple key residues within HDAC2 internal cavity that contribute to the
ligand binding. Dynamics behavior of the complex suggests that this candidate ligand conveys its
uniquely high affinity by interacting with both the entrance and the internal cavity of the active site
and by dampening the fluctuation of the loops surrounding the entry point. These discovered features
could also prove useful in guiding future designs of other selective and potent inhibitors against
HDAC2.
Start & End Page 
 135 - 149
Received Date 
 2020-06-10
Revised Date 
Accepted Date 
 2020-07-22
Full Text 
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File Supplemental 
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Keyword 
 histone deacetylase, inhibitor, molecular dynamics simulation, molecular mechanics, drug discovery, HIV
Volume 
 Vol.48 No.1 (January 2021)
DOI 
Citation 
 Kittivibul K., Tateing S. and Suree N., Discovery and Dynamics Behavior of a New Isoform-Selective Histone Deacetylase 2 Inhibitor Targeting the Active-Site Internal Cavity, Chiang Mai J. Sci., 2021; 48(1): 135-149.
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