Virtual screening of small molecules databases for discovery of novel PARP-1 inhibitors: combination of in silico and in vitro studies

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dc.authoridMestanoglu, Mert/0000-0002-7984-5959
dc.authoridYurtsever, Mine/0000-0001-6504-7182
dc.authoridDurdagi, Serdar/0000-0002-0426-0905
dc.authoridEkhteiari Salmas, Ramin/0000-0003-3888-5070
dc.authoridunlu, ayhan/0000-0001-6033-7148
dc.authorwosidBektaş, Muhammet/AAE-5503-2020
dc.authorwosidMestanoglu, Mert/AAH-6147-2019
dc.authorwosidDurdagi, Serdar/B-6862-2009
dc.authorwosidYurtsever, Mine/O-3748-2014
dc.authorwosidDurdagi, Serdar/J-1904-2018
dc.authorwosidEkhteiari Salmas, Ramin/J-6401-2016
dc.authorwosidunlu, ayhan/Q-1843-2016
dc.contributor.authorSalmas, Ramin Ekhteiari
dc.contributor.authorUnlu, Ayhan
dc.contributor.authorBektas, Muhammet
dc.contributor.authorYurtsever, Mine
dc.contributor.authorMestanoglu, Mert
dc.contributor.authorDurdagi, Serdar
dc.date.accessioned2024-06-12T11:12:06Z
dc.date.available2024-06-12T11:12:06Z
dc.date.issued2017
dc.departmentTrakya Üniversitesien_US
dc.description.abstractPoly(ADP-ribose) polymerase-1 (PARP-1) enzyme has critical roles in DNA replication repair and recombination. Thus, PARP-1 inhibitors play an important role in the cancer therapy. In the current study, we have performed combination of in silico and in vitro studies in order to discover novel inhibitors against PARP-1 target. Structure-based virtual screening was carried out for an available small molecules database. A total of 257,951 ligands from Otava database were screened at the binding pocket of PARP-1 using high-throughput virtual screening techniques. Filtered structures based on predicted binding energy results were then used in more sophisticated molecular docking simulations (i.e. Glide/standard precision, Glide/XP, induced fit docking - IFD, and quantum mechanics polarized ligand docking - QPLD). Potential high binding affinity compounds that are predicted by molecular simulations were then tested by in vitro methods. Computationally proposed compounds as PARP-1 inhibitors (Otava Compound Codes: 7111620047 and 7119980926) were confirmed by in vitro studies. In vitro results showed that compounds 7111620047 and 7119980926 have IC50 values of 0.56 and 63M against PARP-1 target, respectively. The molecular mechanism analysis, free energy perturbation calculations using long multiple molecular dynamics simulations for the discovered compounds which showed high binding affinity against PARP-1 enzyme, as well as structure-based pharmacophore development (E-pharmacophore) studies were also studied.en_US
dc.description.sponsorshipIstanbul Technical University (ITU) Research Fund; Bilim Akademisi - The Science Academy, Turkey, under the BAGEP programen_US
dc.description.sponsorshipThis work was supported by Istanbul Technical University (ITU) Research Fund. ITU National Computing Center (UHEM) provided us the computer time. This study was also supported by Bilim Akademisi - The Science Academy, Turkey, under the BAGEP program to S.D., and CompecTA provided us computer time and services for part of the study.en_US
dc.identifier.doi10.1080/07391102.2016.1199328
dc.identifier.endpage1915en_US
dc.identifier.issn0739-1102
dc.identifier.issn1538-0254
dc.identifier.issue9en_US
dc.identifier.pmid27315035en_US
dc.identifier.scopus2-s2.0-84978522767en_US
dc.identifier.scopusqualityQ2en_US
dc.identifier.startpage1899en_US
dc.identifier.urihttps://doi.org/10.1080/07391102.2016.1199328
dc.identifier.urihttps://hdl.handle.net/20.500.14551/23046
dc.identifier.volume35en_US
dc.identifier.wosWOS:000403796900005en_US
dc.identifier.wosqualityQ2en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherTaylor & Francis Incen_US
dc.relation.ispartofJournal Of Biomolecular Structure & Dynamicsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectPARP-1en_US
dc.subjectMolecular Docking Simulationsen_US
dc.subjectQM-Polarized Ligand Dockingen_US
dc.subjectHigh-Throughput Virtual Screeningen_US
dc.subjectMM-PBSAen_US
dc.subjectMolecular Dynamics (MD) Simulationsen_US
dc.subjectE-Pharmacophoreen_US
dc.subjectFree Energy Perturbation Calculationsen_US
dc.subjectIn Vitro Colorimetric Assayen_US
dc.subjectResistance-Modifying Agentsen_US
dc.subjectPoly(Adp-Ribose) Polymerase-1en_US
dc.subjectBiological Evaluationen_US
dc.subjectDynamicsen_US
dc.subjectDockingen_US
dc.subjectDesignen_US
dc.subjectIdentificationen_US
dc.subjectBindingen_US
dc.subjectPotenten_US
dc.subjectOptimizationen_US
dc.titleVirtual screening of small molecules databases for discovery of novel PARP-1 inhibitors: combination of in silico and in vitro studiesen_US
dc.typeArticleen_US

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