Targeting SARS-CoV-2 Nsp12/Nsp8 interaction interface with approved and investigational drugs: An in silico structure-based approach

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dc.authoridEmrah Sarıyer / 0000-0003-1721-0314en_US
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.date.accessioned2021-03-24T07:45:46Z
dc.date.available2021-03-24T07:45:46Z
dc.date.issued2020
dc.departmentAÇÜ, Sağlık Hizmetlerien_US
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.
dc.identifier.citationMutlu, O., Uğurel, O. M., Sarıyer, E., Ata, O., İnci, T. G., Uğurel, E., ... & Turgut-Balık, D. (2020). Targeting SARS-CoV-2 Nsp12/Nsp8 interaction interface with approved and investigational drugs: an in silico structure-based approach. Journal of Biomolecular Structure and Dynamics, 1-13.en_US
dc.identifier.doi10.1080/07391102.2020.1819882
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://hdl.handle.net/11494/2798
dc.identifier.urihttps://doi.org/10.1080/07391102.2020.1819882en_US
dc.identifier.volumeArticle in Press
dc.identifier.wosqualityN/A
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.institutionauthorSarıyer, Emrah
dc.language.isoenen_US
dc.publisherTaylor & Francis Incen_US
dc.relation.ispartofJournal of Biomolecular Structure and 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.subjectNsp12en_US
dc.subjectDrug repositioningen_US
dc.subjectRNA dependent RNA polymeraseen_US
dc.titleTargeting SARS-CoV-2 Nsp12/Nsp8 interaction interface with approved and investigational drugs: An in silico structure-based approachen_US
dc.typeArticle

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