key: cord-0954848-08d5cdf4 authors: Lung, Jrhau; Lin, Yu‐Shih; Yang, Yao‐Hsu; Chou, Yu‐Lun; Shu, Li‐Hsin; Cheng, Yu‐Ching; Liu, Hung Te; Wu, Ching‐Yuan title: The potential chemical structure of anti‐SARS‐CoV‐2 RNA‐dependent RNA polymerase date: 2020-03-18 journal: J Med Virol DOI: 10.1002/jmv.25761 sha: 3fdc2568353f81b9069140107542a87bc2a38566 doc_id: 954848 cord_uid: 08d5cdf4 An outbreak of coronavirus disease 2019 (COVID‐19) occurred in Wuhan and it has rapidly spread to almost all parts of the world. For coronaviruses, RNA‐dependent RNA polymerase (RdRp) is an important protease that catalyzes the replication of RNA from RNA template and is an attractive therapeutic target. In this study, we screened these chemical structures from traditional Chinese medicinal compounds proven to show antiviral activity in severe acute respiratory syndrome coronavirus (SARS‐CoV) and the similar chemical structures through a molecular docking study to target RdRp of SARS‐CoV‐2, SARS‐CoV, and Middle East respiratory syndrome coronavirus (MERS‐CoV). We found that theaflavin has a lower idock score in the catalytic pocket of RdRp in SARS‐CoV‐2 (−9.11 kcal/mol), SARS‐CoV (−8.03 kcal/mol), and MERS‐CoV (−8.26 kcal/mol) from idock. To confirm the result, we discovered that theaflavin has lower binding energy of −8.8 kcal/mol when it docks in the catalytic pocket of SARS‐CoV‐2 RdRp by using the Blind Docking server. Regarding contact modes, hydrophobic interactions contribute significantly in binding and additional hydrogen bonds were found between theaflavin and RdRp. Moreover, one π‐cation interaction was formed between theaflavin and Arg553 from the Blind Docking server. Our results suggest that theaflavin could be a potential SARS‐CoV‐2 RdRp inhibitor for further study. this study, we screened these chemical structures from traditional Chinese medicinal compounds proven to show antiviral activity in severe acute respiratory syndrome coronavirus (SARS-CoV) and the similar chemical structures through a molecular docking study to target RdRp of SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV). We found that theaflavin has a lower idock score in the catalytic pocket of RdRp in SARS-CoV-2 (−9.11 kcal/mol), SARS-CoV (−8.03 kcal/mol), and MERS-CoV (−8.26 kcal/mol) from idock. To confirm the result, we discovered that theaflavin has lower binding energy of −8.8 kcal/mol when it docks in the catalytic pocket of SARS-CoV-2 RdRp by using the Blind Docking server. Regarding contact modes, hydrophobic interactions contribute significantly in binding and additional hydrogen bonds were found between theaflavin and RdRp. Moreover, one π-cation interaction was formed between theaflavin and Arg553 from the Blind Docking server. Our results suggest that theaflavin could be a potential SARS-CoV-2 RdRp inhibitor for further study. Ebola virus, SARS-CoV, and MERS-CoV. [3] [4] [5] More importantly, one report indicated that remdesivir improved the critical condition of one COVID-19 patient. 6 Therefore, RdRp could be an attractive therapeutic target for SARS-CoV-2. In China, many traditional Chinese medicinal compounds have been used to treat SARS-CoV and SARS-CoV-2. 3 However, the mechanisms of activity and the efficiency of these compounds remain unclear. Therefore, we screened the chemical structures of clinically used traditional Chinese medicinal compounds with proven antiviral activity against SARS-CoV and their similar chemical structures, using a molecular docking method to target RdRp of SARS-CoV-2. Eighty-three chemical structures from traditional Chinese medicinal compounds and their similar structures were retrieved from ZINC15 database. We used two molecular docking methods for analysis. First, molecular docking and virtual screening was performed using idock download from Github (https://github.com/HongjianLi/idock) in a local Linux machine. Second, the Blind Docking server was used for in silico prediction of the lowest free binding energy. Calculations were carried out with "Achilles" Blind Docking Server, available at: http://bio-hpc.eu/software/blind-docking-server/. The grid box Screening of these chemical structures revealed that theaflavin (ZINC3978446, Figure 2A) Many herbals and compounds used in traditional Chinese medicine have been screened as anti-SARS-CoV therapy. [10] [11] [12] [13] [14] Theaflavin, a polyphenolic compound in black tea, is thought to be responsible for the medicinal value of black tea. Theaflavin and theaflavin gallate derivatives have shown broad-spectrum antiviral activity against several viruses, including influenza A and B viruses and hepatitis C virus. 15, 16 Furthermore, it has been shown that extracts from Pu'er tea and black tea, and theaflavin-3,3′-digallate and 3-isotheaflavin-3-gallate, in the theaflavins family, have potent inhibitory activity against SARS, by inhibiting SARS-CoV 3CL pro activity. 17 In this study, we found that theaflavin was able to dock in the catalytic pocket near the active site of RdRp in SARS-CoV-2, SARS-CoV, and MERS-CoV. Furthermore, theaflavin has the lowest idock score and lower binding energy in the catalytic pocket of SARS-CoV-2 RdRp in the two different molecular docking methods. We also found that theaflavin formed additional hydrogen bonds and π-cation interaction with the catalytic pocket of SARS-CoV-2 RdRp. This may explain why theaflavin had lower idock score than the other chemical structures that we screened. It is possible that theaflavin could inhibit RdRp activity through blocking the active site in the groove. Our results suggest that theaflavin could be used as a lead compound for developing a SARS-CoV-2 inhibitor that targets RdRp. However, the exact in vivo effect is still unclear, and further research is needed to confirm the mechanism whereby theaflavin target SARS-CoV-2. Analyzing the epidemiological outbreak of COVID-19: a visual exploratory data analysis (EDA) approach Learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV Potential interventions for novel coronavirus in China: a systematic review The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus pii: jbc.AC120.013056 Mechanism of inhibition of Ebola virus RNA-dependent RNA polymerase by remdesivir. Viruses First case of 2019 novel coronavirus in the United States Protein structure modeling with MODELLER UCSF Chimera-a visualization system for exploratory research and analysis SWISS-MODEL: homology modelling of protein structures and complexes Effect of integrated traditional Chinese and Western medicine on SARS: a review of clinical evidence Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus Biflavonoids from Torreya nucifera displaying SARS-CoV 3CL(pro) inhibition Tanshinones as selective and slowbinding inhibitors for SARS-CoV cysteine proteases Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells Comparison of in vitro antiviral activity of tea polyphenols against influenza A and B viruses and structure-activity relationship analysis Theaflavins, polyphenols of black tea, inhibit entry of hepatitis C virus in cell culture Inhibition of SARS-CoV 3C-like protease activity by theaflavin-3,3′-digallate (TF3) The potential chemical structure of anti-SARS-CoV-2 RNAdependent RNA polymerase The authors declare that there are no conflict of interests. All data and materials are contained and described within the manuscript. http://orcid.org/0000-0001-6172-6647