Homology modeling andin silicodesign of novel and potential dual-acting inhibitors of human histone deacetylases HDAC5 and HDAC9 isozymes

dc.contributor.authorYelekçi, Kemal
dc.contributor.authorYelekçi, Kemal
dc.date.accessioned2020-08-14T11:54:32Z
dc.date.available2020-08-14T11:54:32Z
dc.date.issued2020
dc.departmentFakülteler, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoinformatik ve Genetik Bölümüen_US
dc.description.abstractHistone 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. Sarmaen_US
dc.identifier.citation9
dc.identifier.doi10.1080/07391102.2020.1798812en_US
dc.identifier.issn0739-1102en_US
dc.identifier.issn1538-0254en_US
dc.identifier.issn0739-1102
dc.identifier.issn1538-0254
dc.identifier.pmid32715940en_US
dc.identifier.scopus2-s2.0-85088598706en_US
dc.identifier.scopusqualityQ2
dc.identifier.urihttps://hdl.handle.net/20.500.12469/3173
dc.identifier.urihttps://doi.org/10.1080/07391102.2020.1798812
dc.identifier.wosWOS:000552541100001en_US
dc.identifier.wosqualityN/A
dc.institutionauthorElmezayen, Ammar D.en_US
dc.institutionauthorYelekçi, Kemalen_US
dc.language.isoenen_US
dc.relation.journalJournal of Biomolecular Structure & Dynamicsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/embargoedAccessen_US
dc.subjectHDAC5en_US
dc.subjectHDAC9en_US
dc.subjectHomology modelen_US
dc.subjectMolecular dockingen_US
dc.subjectKnown inhibitorsen_US
dc.subjectVirtual screeningen_US
dc.subjectMD simulationen_US
dc.titleHomology modeling andin silicodesign of novel and potential dual-acting inhibitors of human histone deacetylases HDAC5 and HDAC9 isozymesen_US
dc.typeArticleen_US
dspace.entity.typePublication
relation.isAuthorOfPublication9407938e-3d31-453b-9199-aaa8280a66c5
relation.isAuthorOfPublication.latestForDiscovery9407938e-3d31-453b-9199-aaa8280a66c5

Files

License bundle

Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.71 KB
Format:
Item-specific license agreed upon to submission
Description: