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dc.contributor.authorLi, Yongfang
dc.contributor.authorZhang, Dong
dc.contributor.authorGao, Xin
dc.contributor.authorWang, Xiaowei
dc.contributor.authorZhang, Lu
dc.date.accessioned2022-05-09T05:49:48Z
dc.date.available2022-05-09T05:49:48Z
dc.date.issued2022-05-03
dc.identifier.citationLi, Y., Zhang, D., Gao, X., Wang, X., & Zhang, L. (2022). 2′- and 3′-Ribose Modifications of Nucleotide Analogues Establish the Structural Basis to Inhibit the Viral Replication of SARS-CoV-2. The Journal of Physical Chemistry Letters, 4111–4118. https://doi.org/10.1021/acs.jpclett.2c00087
dc.identifier.issn1948-7185
dc.identifier.issn1948-7185
dc.identifier.pmid35503748
dc.identifier.doi10.1021/acs.jpclett.2c00087
dc.identifier.urihttp://hdl.handle.net/10754/676679
dc.description.abstractInhibition of RNA-dependent RNA polymerase (RdRp) by nucleotide analogues with ribose modification provides a promising antiviral strategy for the treatment of SARS-CoV-2. Previous works have shown that remdesivir carrying 1'-substitution can act as a "delayed chain terminator", while nucleotide analogues with 2'-methyl group substitution could immediately terminate the chain extension. However, how the inhibition can be established by the 3'-ribose modification as well as other 2'-ribose modifications is not fully understood. Herein, we have evaluated the potential of several adenosine analogues with 2'- and/or 3'-modifications as obligate chain terminators by comprehensive structural analysis based on extensive molecular dynamics simulations. Our results suggest that 2'-modification couples with the protein environment to affect the structural stability, while 3'-hydrogen substitution inherently exerts "immediate termination" without compromising the structural stability in the active site. Our study provides an alternative promising modification scheme to orientate the further optimization of obligate terminators for SARS-CoV-2 RdRp.
dc.description.sponsorshipFinancial support from the National Key R&D program of China (2021YFA1502300), the National Natural Science Foundation of China (21733007), and the NSFC/RGC Joint Research Scheme 2020/2021 (N_HKUST635/20). This research made use of the resources of the Supercomputing Laboratory at King Abdullah University of Science & Technology (KAUST).
dc.publisherAmerican Chemical Society (ACS)
dc.relation.urlhttps://pubs.acs.org/doi/10.1021/acs.jpclett.2c00087
dc.rightsThis document is the Accepted Manuscript version of a Published Work that appeared in final form in The Journal of Physical Chemistry Letters, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jpclett.2c00087.
dc.title2′- and 3′-Ribose Modifications of Nucleotide Analogues Establish the Structural Basis to Inhibit the Viral Replication of SARS-CoV-2
dc.typeArticle
dc.contributor.departmentComputational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
dc.contributor.departmentComputer Science Program
dc.contributor.departmentComputational Bioscience Research Center (CBRC)
dc.contributor.departmentComputer, Electrical and Mathematical Science and Engineering (CEMSE) Division
dc.identifier.journalThe Journal of Physical Chemistry Letters
dc.rights.embargodate2023-05-03
dc.eprint.versionPost-print
dc.contributor.institutionState Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, 350002, Fuzhou, Fujian, China
dc.contributor.institutionUniversity of Chinese Academy of Sciences, 100864, Beijing, China
dc.contributor.institutionDepartment of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Kowloon 999077, Hong Kong
dc.contributor.institutionFujian Provincial Key Laboratory of Theoretical and Computational Chemistry, 361005, Xiamen, Fujian, China
dc.identifier.pages4111-4118
kaust.personGao, Xin
kaust.acknowledged.supportUnitSupercomputing Laboratory


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