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Homology modeling of human histone deacetylase 10 and design of potential selective inhibitors

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Date
2019
Author
Uba, Abdullahi Ibrahim
Yelekçi, Kemal
Abstract
Histone deacetylases (HDACs) are implicated in the pathology of various cancers, and their pharmacological blockade has proven to be promising in reversing the malignant phenotypes. However, lack of crystal structures of some of the human HDAC isoforms (e.g., HDAC10) hinders the design of the isoform-selective inhibitor. Here, the recently solved X-ray crystal structure of Danio rerio (zebrafish) HDAC10 (Protein Data Bank (PDB) ID; 5TD7, released on 24 May 2017) was retrieved from the PDB and used as a template structure to model the three-dimensional structure of human HDAC10. The overall quality of the best model (M0017) was assessed by computing its z-score-a measure of the deviation of the total energy of the structure with respect to an energy distribution derived from random conformations and by docking of known HDAC10 inhibitors to its catalytic cavity. Furthermore, to identify potential HDAC10-selective inhibitor ligand-based virtual screening was carried out against the ZINC database. The free modeled structure of HDAC10 and its complexes with quisinostat and the highest-ranked compound ZINC19749069 were submitted to molecular dynamics simulation. The comparative analysis of root-mean-squared deviation, root-mean-squared fluctuation, radius of gyration (Rg), and potential energy of these systems showed that HDAC10-ZINC19749069 complex remained the most stable over time. Thus, M0017 could be potentially used for structure-based inhibitor against HDAC10, and ZINC19749069 may provide a scaffold for further optimization. Communicated by Ramaswamy H. Sarma

Source

Journal Of Biomolecular Structure & Dynamics

Issue

14

Volume

37

Pages

3627-3636

URI

https://doi.org/10.1080/07391102.2018.1521747
https://hdl.handle.net/20.500.12469/3539

Collections

  • Araştırma Çıktıları / Scopus [1565]
  • Araştırma Çıktıları / WOS [1518]
  • Biyoinformatik ve Genetik / Bioinformatics and Genetics [220]

Keywords

Ligand-based virtual screening
Molecular docking
Molecular dynamics simulation
HDAC10-selective inhibitors
Homology modeling

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DSpace software copyright © 2002-2015  DuraSpace
Contact Us | Send Feedback
Theme by 
@mire NV