key: cord-0780942-mh95ueih authors: Yu, Ran; Chen, Liang; Lan, Rong; Shen, Rong; Li, Peng title: Computational screening of antagonist against the SARS-CoV-2 (COVID-19) coronavirus by molecular docking date: 2020-05-08 journal: Int J Antimicrob Agents DOI: 10.1016/j.ijantimicag.2020.106012 sha: 1e8f96e147d2c40bf7f5448cc810e3f6d64ac7e2 doc_id: 780942 cord_uid: mh95ueih Abstract In the current episode of novel coronavirus (SARS-CoV-2) spreads, antiviral drug discovery is of great importance. Auto dock vina was used to screen potential drugs by molecular docking with the structure protein and non-structure protein sites of new coronavirus. Ribavirin, a common antiviral drug, as well as remdesivir, chloroquine and luteolin, were all studied. Honeysuckle is generally believed to have antiviral effect in traditional Chinese medicine, the main flavonoid in which is Luteolin. In the study, it was found luteolin could bind to the same sites of main protease of SARS-CoV-2 as the control molecular with a high affinity. Chloroquine, was proved clinically effective, can bind to the main protease, which may be the possible antiviral mechanism. And the study was restricted to molecular docking without validation by MD simulations. Interactions with the main protease may play a key role in in fighting against viruses. Luteolin is a potential antiviral molecule worthy of attention. Recently, the novel coronavirus (2019-nCoV) [1] emerged in Hubei province, P.R. China [2, 3] . The whole-genome sequence of 2019-nCoV was first released on January 10, 2020 [4] . 2019-nCoV has a wide range of infection to mammals, including humans. This characteristic of transmission leads to the possibility of transmission from animals to people. The 2019-nCoV, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmittable and could lead to mild to severe respiratory tract infections [5] . The spread of 2019-nCoV has drawn great attentions 3 and concerns worldwide, since 2003 humans have faced two coronavirus-related crises [6] . Severe acute respiratory syndrome coronavirus (SARS-CoV) broke out in 2003 and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) emerged in the Arabian Peninsula in 2012 with a fatality rate of 35% [7] . Coronaviruses (CoVs) encode replicase complex (ORF1ab), express in the form of polyproteins (pp), which synthesis the non-structural proteins (nsp) and four structural proteins, namely spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins [8] during proteolytic processing [9] . The main protease (3CL protease) is a key enzyme in the processing of polyproteins pp1a and pp1ab. ORF1a and ORF1ab are cleaved by papain-like protease (PLpro, nsp3) and 3C-like protease (3CLpro, nsp5) to produce the nsp [10] . Due to the important function of SARS-CoV 3CL protease, it is considered as an active target for the antiviral drug. Many 3CL protease inhibitors have been reported over the past decade [11] and a variety of inhibitors were found through screening and structure-based design [12] . PLpro is an indispensable enzyme in the virus replication and infection of the host, and also has been an important target for coronavirus inhibitors. A recent study showed that 2019-nCoV also use angiotensin-converting enzyme 2 (ACE2) as entry receptor to go into the host cells [13] . The spike plays a crucial role during the virus' entry to the host cells [14] . S protein, a type I glycoprotein, on the surface of the virus, can assist virus to bind to host acceptor, which has attracted great attention because of its function in receptor binding. The receptor binding domain (RBD) of spike protein is in charge of the binding to host. 72% of the amino acid sequences in the RBDs from SARA-CoV and 2019 nCoV are identical. However, as to 2019-nCoV, the rigid prolyl residues is replaced with a distinct loop with flexible glycyl residues [15] . A unique phenylalanine F486 in the loop can penetrate into a the hydrophobic pocket of (ACE2) [16] , may play the key role in acceptor recognition. Nsp12 is a viral RNA-dependent RNA polymerase (RdRp), together with co-factors nsp7 and nsp8 possessing high polymerase activity. Four functional proteins in 2019-nCoV: main protease (3CLpro), RdRp, PLpro, and spike were all studied as the targets of potential drugs. Up to now, there is no approved special antiviral drug available to be used against COVID-19. The fastest way to find drugs anti-2019-nCoV is to screen drugs which were commonly used in clinic. 4 During the treatment of patients infected by SARS-CoV-2 [17] chloroquine draw great attention, which was made by Bayer in Germany in 1934 as the replacement of natural antimalarial drugs. Chloroquine was found to be efficient on SARS-CoV-2 [18, 19] . The mechanism of chloroquine is inhibiting quinone reductase 2, a structural similarity of UDP-N-acetylglucosamine 2-epimerases which is involved in the biosynthesis of sialic acids. The possible interference of chloroquine with sialic acid biosynthesis could account for the broad antiviral spectrum [19] . Chloroquine can also impair early stage of virus replication by interfering with the pH-dependent endosome-mediated viral entry of enveloped viruses as well as the post-translational modification of viral proteins. But the mechanism of action of chloroquine in anti-2019-nCoV is not clear. Ribavirin is a traditional antiviral drug widely used in clinic for treating a variety of viral infections, but for SARS, ribavirin showed no significant effect [20] . The new antiviral drug remdesivir were found to be effective in preventing replication of this virus [21] . Remdesivir [22] is now as a possible therapeutic option for the COVID-19 [23] . Lianhuaqingwen (LH) as traditional Chinese medicine (TCM) compound preparation has been used to treat influenza and exerted broad-spectrum antiviral effects on a series of influenza viruses. LH showed anti-2019nCoV activity in the treatment [24] . Honeysuckle and forsythia are commonly used as antiviral ingredients in TCM, which were also included in LH. The kinds and quantity of active components in TCM formula is vital for the function of the preparation. Forsythia has long been used as an antipyretic, anti-inflammatory and anti-infectious agent in East Asia [25] . The compounds in forsythia showed anti-viral activity against H1N1virus and respiratory syncytial virus (RSV) [26] [27] [28] [29] . Honeysuckle are traditional medicine used in China [30] . The major ingredients in Honeysuckle exhibit antibacterial and antiviral [31, 32] activities. Luteolin is the main flavonoid in Honeysuckle [33] . At this situation, TCM can contribute as an alternative treatment. In 2003, TCM was widely used to treat severe acute respiratory syndrome (SARS). The high similarity between 2019 nCoV and SARS in genomic and structural characterization suggesting that TCM may have potential use in the current outbreak [34] . In this study, the binding of chloroquine, remdesivir, ribavirin and luteolin with main proteins of 2019-nCoV 5 (3CL protease, PLpro, RdRp, and spike protein) were carried out by computational methods. The newly-emerged SARS-CoV-2 nucleotide gene (NC_045512.2) was retrieved from the National Center for Biotechnology Information (NCBI) nucleotide database. 6 AutoDock Vina software was utilized in all the docking experiments, with the optimized model as the docking target. The screening method is restricted to molecular docking, and molecular dynamics simulation has not been carried out yet. Remdesivir and ribavirin are all RdRp antagonists. Remdesivir could effectively fight against the new coronavirus, however, ribavirin is invalid. Molecular docking was used to study the binding difference between the two molecules. Chloroquine was proved to be clinically effective, and its molecular target should be further studied. At N3 molecule is the ligand molecule isolated from the crystal structure of 3CL protease, which was used as the binding site control. According to the analysis of docking results (Fig. 1) The ligand P85 of PLpro was used as control. 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