Exploration of the binding pocket of histone deacetylases: the design of potent and isoform-selective inhibitors

dc.contributor.authorYelekçi, Kemal
dc.contributor.authorYelekçi, Kemal
dc.date.accessioned2020-08-25T09:24:07Zen_US
dc.date.available2020-08-25T09:24:07Zen_US
dc.date.issued2017en_US
dc.departmentFakülteler, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoinformatik ve Genetik Bölümüen_US
dc.description.abstractHistone deacetylases (HDACs) are enzymes that act on histone proteins to remove the acetyl group and thereby regulate the chromatin state. HDACs act not only on histone protein but also nonhistone proteins that are key players in cellular processes such as the cell cycle, signal transduction, apoptosis, and more. “Classical” HDACs have been shown to be promising targets for anticancer drug design and development. However, the selectivity of HDAC inhibitors for HDAC isoforms remains the motivation of current research in this field. Here, we explored Class I HDACs and HDAC6 by sequence alignment and structural superimposition, catalytic channel extraction, and identification of critical residues involved in HDAC catalysis. Based on the general pharmacophore features of known HDAC inhibitors, we developed a library of compounds by scaffold hopping on a fragment hit identified via structurebased virtual screening of the molecular fragment library retrieved from the Otava database. Molecular docking assay revealed five of these compounds to have increased potency and selectivity for HDACs 1 and 2. Furthermore, their predicted absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties were consistent with those of drug-like compounds. With further modelingbased and experimental investigations, we believe that these findings may offer additional potential HDAC inhibitors with improved selectivityen_US
dc.identifier.citation14
dc.identifier.doi10.3906/biy-1701-26en_US
dc.identifier.endpage918en_US
dc.identifier.issn1300-0152en_US
dc.identifier.issn1303-6092en_US
dc.identifier.issn1300-0152
dc.identifier.issn1303-6092
dc.identifier.issue6en_US
dc.identifier.pmid30814855en_US
dc.identifier.scopus2-s2.0-85038422971en_US
dc.identifier.scopusqualityQ2
dc.identifier.startpage901en_US
dc.identifier.trdizinid255577en_US
dc.identifier.urihttps://hdl.handle.net/20.500.12469/3252
dc.identifier.urihttps://search.trdizin.gov.tr/yayin/detay/255577
dc.identifier.volume41en_US
dc.identifier.wosWOS:000418253100006en_US
dc.identifier.wosqualityQ3
dc.institutionauthorAuba, Budullahi İbrahimen_US
dc.language.isoenen_US
dc.publisherTübitaken_US
dc.relation.journalTurkish Journal of Biologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectScaffold hoppingen_US
dc.subjectMolecular dockingen_US
dc.subjectADMET analysisen_US
dc.subjectPotent and isoform-selective HDAC inhibitorsen_US
dc.subjectAnticancer agentsen_US
dc.titleExploration of the binding pocket of histone deacetylases: the design of potent and isoform-selective inhibitorsen_US
dc.typeArticleen_US
dspace.entity.typePublication
relation.isAuthorOfPublication9407938e-3d31-453b-9199-aaa8280a66c5
relation.isAuthorOfPublication.latestForDiscovery9407938e-3d31-453b-9199-aaa8280a66c5

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