In silico investigation of PARP-1 catalytic domains in holo and apo states for the design of high-affinity PARP-1 inhibitors

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dc.authoridNoskov, Sergei/0000-0001-7769-335X
dc.authoridunlu, ayhan/0000-0001-6033-7148
dc.authoridEkhteiari Salmas, Ramin/0000-0003-3888-5070
dc.authoridDurdagi, Serdar/0000-0002-0426-0905
dc.authoridYurtsever, Mine/0000-0001-6504-7182
dc.authorwosidNoskov, Sergei Y/B-3654-2010
dc.authorwosidDurdagi, Serdar/B-6862-2009
dc.authorwosidunlu, ayhan/Q-1843-2016
dc.authorwosidEkhteiari Salmas, Ramin/J-6401-2016
dc.authorwosidDurdagi, Serdar/J-1904-2018
dc.authorwosidYurtsever, Mine/O-3748-2014
dc.contributor.authorSalmas, Ramin Ekhteiari
dc.contributor.authorUnlu, Ayhan
dc.contributor.authorYurtsever, Mine
dc.contributor.authorNoskov, Sergei Y.
dc.contributor.authorDurdagi, Serdar
dc.date.accessioned2024-06-12T11:08:09Z
dc.date.available2024-06-12T11:08:09Z
dc.date.issued2016
dc.departmentTrakya Üniversitesien_US
dc.description.abstractThe rational design of high-affinity inhibitors of poly-ADP-ribose polymerase-1 (PARP-1) is at the heart of modern anti-cancer drug design. While relevance of enzyme to DNA repair processes in cellular environment is firmly established, the structural and functional understanding of the main determinants for high-affinity ligands controlling PARP-1 activity is still lacking. The conserved active site of PARP-1 represents an ideal target for inhibitors and may offer a novel target at the treatment of breast cancer. To fill the gap in the structural knowledge, we report on the combination of molecular dynamics (MD) simulations, principal component analysis (PCA), and conformational analysis that analyzes in great details novel binding mode for a number of inhibitors at the PARP-1. While optimization of the binding affinity for original target is an important goal in the drug design, many of the promising molecules for treatment of the breast cancer are plagued by significant cardiotoxicity. One of the most common side-effects reported for a number of polymerase inhibitors is its off-target interactions with cardiac ion channels and hERG1 channel, in particular. Thus, selected candidate PARP-1 inhibitors were also screened in silico at the central cavities of hERG1 potassium ion channel.en_US
dc.description.sponsorshipTurkish Scientific and Technical Research Council (TUBITAK) ULAKBIM High Performance Computing Center; Bilim Akademisi - The Science Academy, Turkey, under the BAGEP programen_US
dc.description.sponsorshipPart of computations for the work described in this paper was supported by Turkish Scientific and Technical Research Council (TUBITAK) ULAKBIM High Performance Computing Center. S.D. acknowledges support from Bilim Akademisi - The Science Academy, Turkey, under the BAGEP program.en_US
dc.identifier.doi10.3109/14756366.2015.1005011
dc.identifier.endpage120en_US
dc.identifier.issn1475-6366
dc.identifier.issn1475-6374
dc.identifier.issue1en_US
dc.identifier.pmid26083304en_US
dc.identifier.scopus2-s2.0-84953205106en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage112en_US
dc.identifier.urihttps://doi.org/10.3109/14756366.2015.1005011
dc.identifier.urihttps://hdl.handle.net/20.500.14551/22318
dc.identifier.volume31en_US
dc.identifier.wosWOS:000367555300013en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherTaylor & Francis Ltden_US
dc.relation.ispartofJournal Of Enzyme Inhibition And Medicinal Chemistryen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectMD Simulationsen_US
dc.subjectMolecular Modelingen_US
dc.subjectPARP-1en_US
dc.subjectPoly(Adp-Ribose) Polymeraseen_US
dc.subjectBreast-Canceren_US
dc.subjectMolecular-Dynamicsen_US
dc.subjectCrystal-Structuresen_US
dc.subjectPotent Inhibitorsen_US
dc.subjectDrug-Bindingen_US
dc.subjectProteinen_US
dc.subjectPredictionen_US
dc.subjectDiscoveryen_US
dc.subjectInsightsen_US
dc.titleIn silico investigation of PARP-1 catalytic domains in holo and apo states for the design of high-affinity PARP-1 inhibitorsen_US
dc.typeArticleen_US

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