DINC-COVID: A webserver for ensemble docking with flexible SARS-CoV-2 proteins

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dc.citation.articleNumber104943en_US
dc.citation.journalTitleComputers in Biology and Medicineen_US
dc.citation.volumeNumber139en_US
dc.contributor.authorHall-Swan, Sarahen_US
dc.contributor.authorDevaurs, Didieren_US
dc.contributor.authorRigo, Mauricio M.en_US
dc.contributor.authorAntunes, Dinler A.en_US
dc.contributor.authorKavraki, Lydia E.en_US
dc.contributor.authorZanatta, Geancarloen_US
dc.date.accessioned2021-11-11T19:30:20Zen_US
dc.date.available2021-11-11T19:30:20Zen_US
dc.date.issued2021en_US
dc.description.abstractAn unprecedented research effort has been undertaken in response to the ongoing COVID-19 pandemic. This has included the determination of hundreds of crystallographic structures of SARS-CoV-2 proteins, and numerous virtual screening projects searching large compound libraries for potential drug inhibitors. Unfortunately, these initiatives have had very limited success in producing effective inhibitors against SARS-CoV-2 proteins. A reason might be an often overlooked factor in these computational efforts: receptor flexibility. To address this issue we have implemented a computational tool for ensemble docking with SARS-CoV-2 proteins. We have extracted representative ensembles of protein conformations from the Protein Data Bank and from in silico molecular dynamics simulations. Twelve pre-computed ensembles of SARS-CoV-2 protein conformations have now been made available for ensemble docking via a user-friendly webserver called DINC-COVID (dinc-covid.kavrakilab.org). We have validated DINC-COVID using data on tested inhibitors of two SARS-CoV-2 proteins, obtaining good correlations between docking-derived binding energies and experimentally-determined binding affinities. Some of the best results have been obtained on a dataset of large ligands resolved via room temperature crystallography, and therefore capturing alternative receptor conformations. In addition, we have shown that the ensembles available in DINC-COVID capture different ranges of receptor flexibility, and that this diversity is useful in finding alternative binding modes of ligands. Overall, our work highlights the importance of accounting for receptor flexibility in docking studies, and provides a platform for the identification of new inhibitors against SARS-CoV-2 proteins.en_US
dc.identifier.citationHall-Swan, Sarah, Devaurs, Didier, Rigo, Mauricio M., et al.. "DINC-COVID: A webserver for ensemble docking with flexible SARS-CoV-2 proteins." <i>Computers in Biology and Medicine,</i> 139, (2021) Elsevier: https://doi.org/10.1016/j.compbiomed.2021.104943.en_US
dc.identifier.digital1-s2-0-S001048252100737X-mainen_US
dc.identifier.doihttps://doi.org/10.1016/j.compbiomed.2021.104943en_US
dc.identifier.urihttps://hdl.handle.net/1911/111646en_US
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.rightsThis is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).en_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/).en_US
dc.titleDINC-COVID: A webserver for ensemble docking with flexible SARS-CoV-2 proteinsen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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