The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which was first reported in Wuhan province of China, has become a deadly pandemic causing alarmingly high morbidity and mortality. In the absence of new targeted drugs and vaccines against SARS-CoV-2 at present, the choices for effective treatments are limited. Therefore, considering the exigency of the situation, we focused on identifying the available approved drugs as potential inhibitor against the promising Coronavirus drug target, the Main Protease, using computer-aided methods. We created a library of U. S. Food and Drug Administration approved anti-microbial drugs and virtually screened it against the available crystal structures of Main Protease of the virus. The study revealed that Viomycin showed the highest-CDocker energy after docking at the active site of SARS-CoV-2 Main Protease. It is noteworthy that Viomycin showed higher-CDocker energy as compared to the drugs currently under clinical trial for SARS-CoV-2 treatment viz. Ritonavir and Lopinavir. Additionally, Viomycin formed higher number of H-bonds with SARS-CoV-2 Main Protease than its co-crystallised inhibitor compound N3. Molecular dynamics simulation further showed that Viomycin embedded deeply inside the binding pocket and formed robust binding with SARS-CoV-2 Main Protease. Therefore, we propose that Viomycin may act as a potential inhibitor of the Main Protease of SARS-CoV-2. Further optimisations with the drug may support the much-needed rapid response to mitigate the pandemic.

Although vaccine development is being undertaken at a breakneck speed, there is currently no effective antiviral drug for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. Therefore, the present study aims to explore the possibilities offered by naturally available and abundant flavonoid compounds, as a prospective antiviral drug to combat the virus. A library of 44 citrus flavonoids was screened against the highly conserved Main Protease (M pro) of SARS-CoV-2 using molecular docking. The compounds which showed better CDocker energy than the co-crystal inhibitor of M pro were further revalidated by flexible docking within the active site; followed by assessment of drug likeness and toxicity parameters. The non-toxic compounds were further subjected to molecular dynamics simulation and predicted activity (IC 50) using 3D-QSAR analysis. Subsequently, hydrogen bonds and dehydration analysis of the best compound were performed to assess the binding affinity to M pro. It was observed that out of the 44 citrus flavonoids, five compounds showed lower binding energy with M pro than the co-crystal ligand. Moreover, these compounds also formed H-bonds with two important catalytic residues His41 and Cys145 of the active sites of M pro. Three compounds which passed the drug likeness filter showed stable conformation during MD simulations. Among these, the lowest predicted IC 50 value was observed for Taxifolin. Therefore, this study suggests that Taxifolin, could be a potential inhibitor against SARS-CoV-2 main protease and can be further analysed by in vitro and in vivo experiments for management of the ongoing pandemic.

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In view of the potential of traditional plant-based remedies (or phytomedicines) in the management of COVID-19, the present investigation was aimed at finding novel anti-SARS-CoV-2 molecules by in silico screening of bioactive phytochemicals (database) using computational methods and drug repurposing approach. A total of 160 compounds belonging to various phytochemical classes (flavonoids, limonoids, saponins, triterpenoids, steroids etc.) were selected (as initial hits) and screened against three specific therapeutic targets (Mpro/ 3CLpro, PLpro and RdRp) of SARS-CoV-2 by docking, molecular dynamics simulation and drug-likeness/ADMET studies. From our studies, six phytochemicals were identified as notable ant-SARS-CoV-2 agents (best hit molecules) with promising inhibitory effects effective against protease (Mpro and PLpro) and polymerase (RdRp) enzymes. These compounds are namely, ginsenoside Rg2, saikosaponin A, somniferine, betulinic acid, soyasapogenol C and azadirachtin A. On the basis of binding modes and dynamics studies of protein-ligand intercations, ginsenoside Rg2, saikosaponin A, somniferine were found to be the most potent ( in silico ) inhibitors potentially active against Mpro, PLpro and RdRp, respectively. The present investigation can be directed towards further experimental studies in order to confirm the anti-SARS-CoV-2 efficacy along with toxicities of identified phytomolecules.

Graphic abstract The Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus, SARS-CoV-2, has recently emerged as a pandemic. Here, an attempt has been made through in-silico high throughput screening to explore the antiviral compounds from traditionally used plants for antiviral treatments in India namely, Tea, Neem and Turmeric, as potential inhibitors of two widely studied viral proteases, main protease (Mpro) and papain-like protease (PLpro) of the SARS-CoV-2. Molecular docking study using BIOVIA Discovery Studio 2018 revealed, (−)-epicatechin-3-O-gallate (ECG), a tea polyphenol has a binding affinity toward both the selected receptors, with the lowest CDocker energy − 46.22 kcal mol −1 for SARS-CoV-2 Mpro and CDocker energy − 44.72 kcal mol −1 for SARS-CoV-2 PLpro, respectively. The SARS-CoV-2 Mpro complexed with (−)-epicatechin-3-O-gallate, which had shown the best binding affinity was subjected to molecular dynamics simulations to validate its binding affinity, during which, the root-mean-square-deviation values of SARS-CoV-2 Mpro–Co-crystal ligand (N3) and SARS-CoV-2 Mpro- (−)-epicatechin-3-O-gallate systems were found to be more stable than SARS-CoV-2 Mpro system. Further, (−)-epicatechin-3-O-gallate was subjected to QSAR analysis which predicted IC 50 of 0.3281 nM against SARS-CoV-2 Mpro. Overall, (−)-epicatechin-3-O-gallate showed a potential binding affinity with SARS-CoV-2 Mpro and could be proposed as a potential natural compound for COVID-19 treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s11030-021-10211-9.