Identification of Potential Isoform-Selective Histone Deacetylase Inhibitors for Cancer Therapy: a Combined Approach of Structure-Based Virtual Screening Admet Prediction and Molecular Dynamics Simulation Assay

dc.contributor.author Uba, Abdullahi İbrahim
dc.contributor.author Yelekçi, Kemal
dc.contributor.author Yelekçi, Kemal
dc.contributor.other Molecular Biology and Genetics
dc.date.accessioned 2019-06-27T08:01:09Z
dc.date.available 2019-06-27T08:01:09Z
dc.date.issued 2018
dc.department Fakülteler, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoinformatik ve Genetik Bölümü en_US
dc.description.abstract Histone deacetylases (HDACs) have gained increased attention as targets for anticancer drug design and development. HDAC inhibitors have proven to be effective for reversing the malignant phenotype in HDAC-dependent cancer cases. However lack of selectivity of the many HDAC inhibitors in clinical use and trials contributes to toxicities to healthy cells. It is believed that the continued identification of isoform-selective inhibitors will eliminate these undesirable adverse effects - a task that remains a major challenge to HDAC inhibitor designs. Here in an attempt to identify isoform-selective inhibitors a large compound library containing 2703000 compounds retrieved from Otava database was screened against class I HDACs by exhaustive approach of structure-based virtual screening using rDOCK and Autodock Vina. A total of 41 compounds were found to show high-isoform selectivity and were further redocked into their respective targets using Autodock4. Thirty-six compounds showed remarkable isoform selectivity and passed drug-likeness and absorption distribution metabolism elimination and toxicity prediction tests using ADMET Predictor and admetSAR. Furthermore to study the stability of ligand binding modes 10ns-molecular dynamics (MD) simulations of the free HDAC isoforms and their complexes with respective best-ranked ligands were performed using nanoscale MD software. The inhibitors remained bound to their respective targets over time of the simulation and the overall potential energy root-mean-square deviation root-mean-square fluctuation profiles suggested that the detected compounds may be potential isoform-selective HDAC inhibitors or serve as promising scaffolds for further optimization towards the design of selective inhibitors for cancer therapy. en_US]
dc.identifier.citationcount 36
dc.identifier.doi 10.1080/07391102.2017.1384402 en_US
dc.identifier.endpage 3245
dc.identifier.issn 0739-1102 en_US
dc.identifier.issn 1538-0254 en_US
dc.identifier.issn 0739-1102
dc.identifier.issn 1538-0254
dc.identifier.issue 12
dc.identifier.pmid 28938863 en_US
dc.identifier.scopus 2-s2.0-85031902133 en_US
dc.identifier.scopusquality Q2
dc.identifier.startpage 3231 en_US
dc.identifier.uri https://hdl.handle.net/20.500.12469/278
dc.identifier.uri https://doi.org/10.1080/07391102.2017.1384402
dc.identifier.volume 36 en_US
dc.identifier.wos WOS:000451749300018 en_US
dc.institutionauthor Yelekçi, Kemal en_US
dc.language.iso en en_US
dc.publisher Taylor & Francis Inc en_US
dc.relation.journal Journal of Biomolecular Structure and Dynamics en_US
dc.relation.publicationcategory Makale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı en_US
dc.rights info:eu-repo/semantics/closedAccess en_US
dc.scopus.citedbyCount 36
dc.subject structure-based virtual screening en_US
dc.subject ADMET analysis en_US
dc.subject MD simulation en_US
dc.subject Isoform-selective HDAC inhibitors en_US
dc.subject Anticancer agents en_US
dc.title Identification of Potential Isoform-Selective Histone Deacetylase Inhibitors for Cancer Therapy: a Combined Approach of Structure-Based Virtual Screening Admet Prediction and Molecular Dynamics Simulation Assay en_US
dc.type Article en_US
dc.wos.citedbyCount 37
dspace.entity.type Publication
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relation.isOrgUnitOfPublication.latestForDiscovery 71ce8622-7449-4a6a-8fad-44d881416546

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