Targeting SARS-CoV-2 Nsp12/Nsp8 interaction interface with approved and investigational drugs: Anin silicostructure-based approach

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dc.contributor.authorMutlu, Özal
dc.contributor.authorUğurel, Osman Mutluhan
dc.contributor.authorSarıyer, Emrah
dc.contributor.authorAta, Oğuz
dc.contributor.authorİnci, Tuğba Gül
dc.contributor.authorUğurel, Erennur
dc.contributor.authorTurgut-Balık, Dilek
dc.date.accessioned2021-05-15T11:33:31Z
dc.date.available2021-05-15T11:33:31Z
dc.date.issued2020
dc.departmentMühendislik ve Doğa Bilimleri Fakültesi, Temel Bilimler Bölümüen_US
dc.descriptionKocer, Sinem/0000-0003-0517-7422; Ugurel, Erennur/0000-0002-5504-660X; Ata, Oguz/0000-0003-4511-7694; SARIYER, Emrah/0000-0003-1721-0314; INCI, Tugba Gul/0000-0002-2801-8021; mutlu, ozal/0000-0003-4551-5780
dc.description.abstractIn this study, the Nsp12-Nsp8 complex of SARS-CoV-2 was targeted with structure-based and computer-aided drug design approach because of its vital role in viral replication. Sequence analysis of RNA-dependent RNA polymerase (Nsp12) sequences from 30,366 different isolates were analysed for possible mutations. FDA-approved and investigational drugs were screened for interaction with both mutant and wild-type Nsp12-Nsp8 interfaces. Sequence analysis revealed that 70.42% of Nsp12 sequences showed conserved P323L mutation, located in the Nsp8 binding cleft. Compounds were screened for interface interaction, any with XP GScores lower than -7.0 kcal/mol were considered as possible interface inhibitors. RX-3117 (fluorocyclopentenyl cytosine) and Nebivolol had the highest binding affinities in both mutant and wild-type enzymes, therefore they were selected and resultant protein-ligand complexes were simulated for analysis of stability over 100 ns. Although the selected ligands had partial mobility in the binding cavity, they were not removed from the binding pocket after 100 ns. The ligand RX-3117 remained in the same position in the binding pocket of the mutant and wild-type enzyme after 100 ns MD simulation. However, the ligand Nebivolol folded and embedded in the binding pocket of mutant Nsp12 protein. Overall, FDA-approved and investigational drugs are able to bind to the Nsp12-Nsp8 interaction interface and prevent the formation of the Nsp12-Nsp8 complex. Interruption of viral replication by drugs proposed in this study should be further tested to pave the way forin vivostudies towards the treatment of COVID-19. Communicated by Ramaswamy H. Sarmaen_US
dc.identifier.doi10.1080/07391102.2020.1819882
dc.identifier.issn0739-1102
dc.identifier.issn1538-0254
dc.identifier.pmid32933378
dc.identifier.scopus2-s2.0-85091083998
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1080/07391102.2020.1819882
dc.identifier.urihttps://hdl.handle.net/20.500.12939/175
dc.identifier.wosWOS:000569452400001
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorUğurel, Osman Mutluhan
dc.language.isoen
dc.publisherTaylor & Francis Incen_US
dc.relation.ispartofJournal of Biomolecular Structure & Dynamics
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectSARS-CoV-2en_US
dc.subjectCOVID-19en_US
dc.subjectMutation Analysisen_US
dc.subjectRNA-Dependent RNA Polymeraseen_US
dc.subjectNsp12en_US
dc.subjectDrug Repositioningen_US
dc.titleTargeting SARS-CoV-2 Nsp12/Nsp8 interaction interface with approved and investigational drugs: Anin silicostructure-based approach
dc.typeArticle

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