Examining the stability of binding modes of the co-crystallized inhibitors of human HDAC8 by molecular dynamics simulation

dc.contributor.authorYelekçi, Kemal
dc.contributor.authorWeako, Jackson
dc.contributor.authorKeskin, Özlem
dc.contributor.authorGürsoy, Attila
dc.contributor.authorYelekçi, Kemal
dc.date.accessioned2019-06-27T08:01:02Z
dc.date.available2019-06-27T08:01:02Z
dc.date.issued2019
dc.departmentFakülteler, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoinformatik ve Genetik Bölümüen_US
dc.description.abstractHistone deacetylase (HDAC) 8 has been implicated as a potential therapeutic target in a variety of cancers neurodegenerative disorders metabolic dysregulation and autoimmune and inflammatory diseases. Several nonselective HDAC inhibitors have been co-crystallized with HDAC8. Molecular dynamics (MD) studies may yield valuable information on the structural stabilities of the complexes over time as determined by various pharmacophore features of the co-crystallized inhibitors. Here using 11 unmodified X-ray crystal structures of human HDAC8 (complexes) structure-based pharmacophore models were built and clustered based on distance - a function of the number of common pharmacophore features and the root-mean-squared displacement between the matching features. Based on this information a total of seven complexes (1T64 1W22 3RQD 3SFF 3F0R 5VI6 and 5FCW) were submitted to unrestrained 50 ns-MD simulations using nanoscale MD (NAMD) software. 1T64 (HDAC8 in complex with TSA) was found to show the highest stability over time presumably because of the TSA's ability to span HDAC8 catalytic channel and form a strong ionic interaction with zinc metal ion. Other stable complexes were 1W22 3SFF 3F0R and 5FCW. However 3RQD and 5VI6 showed relative instability over 50 ns time period. This may be attributed to bulkiness of the capping groups of both largazole thiol and trapoxin A making them unable to fit well into the active site of HDAC8. They rather formed steric clashes with residues on loop regions near the entrance to the channel. Thus 1T64 and similar crystal structures may be good candidates for HDAC8 structural dynamics studies and inhibitor design. Communicated by Ramaswamy H. Sarmaen_US]
dc.identifier.citation12
dc.identifier.doi10.1080/07391102.2019.1615989en_US
dc.identifier.issn0739-1102en_US
dc.identifier.issn1538-0254en_US
dc.identifier.issn0739-1102
dc.identifier.issn1538-0254
dc.identifier.pmid31057077en_US
dc.identifier.scopus2-s2.0-85066095181en_US
dc.identifier.scopusqualityQ2
dc.identifier.urihttps://hdl.handle.net/20.500.12469/221
dc.identifier.urihttps://doi.org/10.1080/07391102.2019.1615989
dc.identifier.wosWOS:000469051900001en_US
dc.identifier.wosqualityN/A
dc.institutionauthorUba, Abdullahi Ibrahimen_US
dc.institutionauthorYelekçi, Kemalen_US
dc.language.isoenen_US
dc.publisherTaylor & Francis Incen_US
dc.relation.journalJournal of Biomolecular Structure and Dynamicsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectHDAC8en_US
dc.subjectCo-crystallized inhibitorsen_US
dc.subjectStability of complexesen_US
dc.subjectMD simulationen_US
dc.titleExamining the stability of binding modes of the co-crystallized inhibitors of human HDAC8 by molecular dynamics simulationen_US
dc.typeArticleen_US
dspace.entity.typePublication
relation.isAuthorOfPublication9407938e-3d31-453b-9199-aaa8280a66c5
relation.isAuthorOfPublication.latestForDiscovery9407938e-3d31-453b-9199-aaa8280a66c5

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