Proposing novel MDM2 inhibitors: Combined physics-driven high-throughput virtual screening and in vitro studies

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dc.authoridYurtsever, Mine/0000-0001-6504-7182
dc.authoridDurdagi, Serdar/0000-0002-0426-0905
dc.authoridAydin, Gulsah/0000-0002-5376-0690
dc.authoridAvsar, Timucin/0000-0001-8841-4811
dc.authoridOrhan, Muge Didem/0000-0001-9014-3838
dc.authorwosidAvsar, Timucin/W-2624-2019
dc.authorwosidYurtsever, Mine/O-3748-2014
dc.authorwosidDurdagi, Serdar/J-1904-2018
dc.contributor.authorAydin, Gulsah
dc.contributor.authorPaksoy, Maide Nur
dc.contributor.authorOrhan, Muge Didem
dc.contributor.authorAvsar, Timucin
dc.contributor.authorYurtsever, Mine
dc.contributor.authorDurdagi, Serdar
dc.date.accessioned2021-12-01T18:49:23Z
dc.date.available2021-12-01T18:49:23Z
dc.date.issued2020
dc.department[Belirlenecek]en_US
dc.description.abstractThe mouse double minute 2 (MDM2) protein acts as a negative regulator of the p53 tumor suppressor. It directly binds to the N terminus of p53 and promotes p53 ubiquitination and degradation. Since the most common p53-suppressing mechanisms involve the MDM2, proposing novel inhibitors has been the focus of many in silico and also experimental studies. Thus, here we screened around 500,000 small organic molecules from Enamine database at the binding pocket of this oncogenic target. The screening was achieved systematically with starting from the high-throughput virtual screening method followed by more sophisticated docking approaches. The initial high number of screened molecules was reduced to 100 hits which then were studied extensively for their therapeutic activity and pharmacokinetic properties using binary QSAR models. The structural and dynamical profiles of the selected molecules at the binding pocket of the target were studied thoroughly by all-atom molecular dynamics simulations. The free energy of the binding of the hit molecules was estimated by the MM/GBSA method. Based on docking simulations, binary QSAR model results, and free energy calculations, 11 compounds (E1-E11) were selected for in vitro studies. HUVEC vascular endothelium, colon cancer, and breast cancer cell lines were used for testing the binding affinities of the identified hits and for further cellular effects on human cancer cell. Based on in vitro studies, six compounds (E1,E2,E5,E6,E9, andE11) in breast cancer cell lines and six compounds (E1,E2,E5,E6,E8, andE10) in colon cancer cell lines were found as active. Our results showed that these compounds inhibit proliferation and lead to apoptosis.en_US
dc.identifier.doi10.1111/cbdd.13694
dc.identifier.endpage700en_US
dc.identifier.issn1747-0277
dc.identifier.issn1747-0285
dc.identifier.issue1en_US
dc.identifier.pmid32691963en_US
dc.identifier.scopus2-s2.0-85088278516en_US
dc.identifier.scopusqualityQ2en_US
dc.identifier.startpage684en_US
dc.identifier.urihttps://doi.org/10.1111/cbdd.13694
dc.identifier.urihttps://hdl.handle.net/20.500.12684/10714
dc.identifier.volume96en_US
dc.identifier.wosWOS:000550342600004en_US
dc.identifier.wosqualityQ3en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakPubMeden_US
dc.indekslendigikaynakScopusen_US
dc.language.isoenen_US
dc.publisherWileyen_US
dc.relation.ispartofChemical Biology & Drug Designen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectdrug designen_US
dc.subjecthybrid methods in virtual screeningen_US
dc.subjectmouse double minute 2 inhibitorsen_US
dc.subjectstructure-based drug designen_US
dc.subjectvirtual screeningen_US
dc.subjectUbiquitin Ligase Activityen_US
dc.subjectAccurate Dockingen_US
dc.subjectProteinen_US
dc.subjectP53en_US
dc.subjectExpressionen_US
dc.subjectPredictionen_US
dc.subjectDiscoveryen_US
dc.subjectGlideen_US
dc.subjectRationalizationen_US
dc.subjectAntagonistsen_US
dc.titleProposing novel MDM2 inhibitors: Combined physics-driven high-throughput virtual screening and in vitro studiesen_US
dc.typeArticleen_US

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