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标题：High-throughput rational design of the remdesivir binding site in the RdRp of SARS-CoV-2: implications for potential resistance
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作者：Aditya K. Padhi ; Rohit Shukla ; Prakash Saudagar 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：1
页码：1-30
DOI：10.1016/j.isci.2020.101992
语种：English
出版社：Elsevier
摘要：SummaryThe use of remdesivir to treat COVID-19 will likely continue before clinical trials are completed. Due to the lengthening pandemic and evolving nature of the virus, predicting potential residues prone to mutation is crucial for the management of remdesivir resistance. Using a rational ligand-based interface design complemented with mutational mapping, we generated a total of 100,000 mutations and provided insight into the functional outcomes of mutations in the remdesivir-binding site in nsp12 subunit of RdRp. After designing 46 residues in the remdesivir-binding site of nsp12, the designs retained 97%–98% sequence identity, suggesting that very few mutations in nsp12 are required for SARS-CoV-2 to attain remdesivir resistance. Several mutants displayed decreased binding affinity to remdesivir, suggesting drug resistance. These hotspot residues had a higher probability of undergoing selective mutation and thus conferring remdesivir resistance. Identifying the potential residues prone to mutation improves our understanding of SARS-CoV-2 drug resistance and COVID-19 pathogenesis.Graphical AbstractDisplay OmittedHighlights•SARS-CoV-2 may acquire mutations in nsp12 to develop remdesivir resistance•Hotspot residues that exhibited the highest potential for mutation were identified•Virus can undergo positive selection and attain resistance with very few mutations•Data is crucial for the understanding and management of drug resistanceBiological Sciences; Microbiology; Virology