当前位置： SCI文献检索 > JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS期刊下所有文献 > Homology modeling and in silico design of novel and potential dual-acting inhibitors of human histone deacetylases HDAC5 and HDAC9 isozymes.

Homology modeling and in silico design of novel and potential dual-acting inhibitors of human histone deacetylases HDAC5 and HDAC9 isozymes.

Abstract：

:Histone deacetylases (HDACs) are a group of enzymes that have prominent and crucial effect on various biological systems, mainly by their suppressive effect on transcription. Searching for inhibitors targeting their respective isoforms without affecting other targets is greatly needed. Some histone deacetylases have no crystal structures, such as HDAC5 and HDAC9. Lacking proper and suitable crystal structure is obstructing the designing of appropriate isoform selective inhibitors. Here in this study, we constructed human HDAC5 and HDAC9 protein models using human HDAC4 (PDB:2VQM_A) as a template by the means of homology modeling approach. Based on the Z-score of the built models, model M0014 of HDAC5 and model M0020 of HDAC9 were selected. The models were verified by MODELLER and validated using the Web-based PROCHECK server. All selected known inhibitors displayed reasonable binding modes and equivalent predicted Ki values in comparison to the experimental binding affinities (Ki/IC50). The known inhibitor Rac26 showed the best binding affinity for HDAC5, while TMP269 showed the best binding affinity for HDAC9. The best two compounds, CHEMBL2114980 and CHEMBL217223, had relatively similar inhibition constants against HDAC5 and HDAC9. The built models and their complexes were subjected to molecular dynamic simulations (MD) for 100 ns. Examining the MD simulation results of all studied structures, including the RMSD, RMSF, radius of gyration and potential energy suggested the stability and reliability of the built models. Accordingly, the results obtained in this study could be used for designing de novo inhibitors against HDAC5 and HDAC9. Communicated by Ramaswamy H. Sarma.

journal_name

J Biomol Struct Dyn

journal_title

Journal of biomolecular structure & dynamics

authors

Elmezayen AD,Yelekçi K

doi

10.1080/07391102.2020.1798812

subject

Has Abstract

pub_date

2020-07-27 00:00:00

pages

1-19

eissn

0739-1102

issn

1538-0254

pub_type

杂志文章

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