The sudden outburst of Coronavirus disease (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses a massive threat to global public health. Currently, no therapeutic drug or vaccine exists to treat COVID-19. Due to the time taking process of new drug development, drug repurposing might be the only viable solution to tackle COVID-19. RNA-dependent RNA polymerase (RdRp) catalyzes SARS-CoV-2 RNA replication and hence, is an obvious target for antiviral drug design. Interestingly, several plant-derived polyphenols effectively inhibit the RdRp of other RNA viruses. More importantly, polyphenols have been used as dietary supplementations for a long time and played beneficial roles in immune homeostasis. We were curious to study the binding of polyphenols with SARS-CoV-2 RdRp and assess their potential to treat COVID-19. Herein, we made a library of polyphenols that have shown substantial therapeutic effects against various diseases. They were successfully docked in the catalytic pocket of RdRp. The investigation reveals that EGCG, theaflavin (TF1), theaflavin-3'-O-gallate (TF2a), theaflavin-3'-gallate (TF2b), theaflavin 3,3'-digallate (TF3), hesperidin, quercetagetin, and myricetin strongly bind to the active site of RdRp. Further, a 150-ns molecular dynamic simulation revealed that EGCG, TF2a, TF2b, TF3 result in highly stable bound conformations with RdRp. The binding free energy components calculated by the MM-PBSA also confirm the stability of the complexes. We also performed a detailed analysis of ADME prediction, toxicity prediction, and target analysis for their druggability. Overall, our results suggest that EGCG, TF2a, TF2b, TF3 can inhibit RdRp and represent an effective therapy for COVID-19.

The recent outbreak of novel "coronavirus disease 2019" (COVID-19) has spread rapidly worldwide, causing a global pandemic. In the present work, we have elucidated the mechanism of binding of two inhibitors, namely a-ketoamide and Z31792168, to SARS-CoV-2 main protease (M pro or 3CL pro ) by using all-atom molecular dynamics simulations and free energy calculations. We calculated the total binding free energy (DG bind ) of both inhibitors and further decomposed DG bind into various forces governing the complex formation using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Our calculations reveal that a-ketoamide is more potent (DG bind ¼ À 9.05 kcal/mol) compared to Z31792168 (DG bind ¼ À 3.25 kcal/mol) against COVID-19 3CL pro . The increase in DG bind for a-ketoamide relative to Z31792168 arises due to an increase in the favorable electrostatic and van der Waals interactions between the inhibitor and 3CL pro . Further, we have identified important residues controlling the 3CL pro -ligand binding from per-residue based decomposition of the binding free energy. Finally, we have compared DG bind of these two inhibitors with the anti-HIV retroviral drugs, such as lopinavir and darunavir. It is observed that a-ketoamide is more potent compared to lopinavir and darunavir. In the case of lopinavir, a decrease in van der Waals interactions is responsible for the lower binding affinity compared to a-ketoamide. On the other hand, in the case of darunavir, a decrease in the favorable intermolecular electrostatic and van der Waals interactions contributes to lower affinity compared to a-ketoamide. Our study might help in designing rational anti-coronaviral drugs targeting the SARS-CoV-2 main protease.

The With-No-Lysine (WNK) kinase is considered to be a master regulator for various cation-chloride cotransporters involved in maintaining cell-volume and ion homeostasis. Here, we have investigated the phosphorylation-induced structural dynamics of the WNK1 kinase bound to an inhibitor via atomistic molecular dynamics simulations. Results from our simulations show that the phosphorylation at Ser382 could stabilize the otherwise flexible activation loop (A-loop). The intrahelix salt-bridge formed between Arg264 and Glu268 in the unphosphorylated system is disengaged after the phosphorylation, and Glu268 reorients itself and forms a stable salt-bridge with Arg348. The dynamic cross-correlation analysis shows that phosphorylation diminishes anticorrelated motions and increases correlated motions between different domains. Structural network analysis reveals that the phosphorylation causes structural rearrangements and shortens the communication path between the αC-helix and catalytic loop, making the binding pocket more suitable for accommodating the ligand. Overall, we have characterized the structural changes in the WNK kinase because of phosphorylation in the A-loop, which might help in designing rational drugs.

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<div>The recent outbreak of novel “coronavirus disease 2019” (COVID-19) has spread rapidly</div><div>worldwide, causing a global pandemic. In the absence of a vaccine or a suitable</div><div>chemotherapeutic intervention, it is an urgent need to develop a new antiviral drug to fight this</div><div>deadly respiratory disease. In the present work, we have elucidated the mechanism of binding</div><div>of two inhibitors, namely α-ketoamide and Z31792168 to SARS-CoV-2 main protease (Mpro</div><div>or 3CLpro) by using all-atom molecular dynamics simulations and free energy calculations. We</div><div>calculated the total binding free energy (ΔGbind) of both inhibitors and further decomposed</div><div>ΔGbind into various forces governing the complex formation using the Molecular</div><div>Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Our calculations reveal</div><div>that α-ketoamide is more potent (ΔGbind= - 9.05 kcal/mol) compared to Z31792168 (ΔGbind= -</div><div>3.25 kcal/mol) against COVID-19 3CLpro. The increase in ΔGbind for α-ketoamide relative to</div><div>Z31792168 arises due to an increase in the favorable electrostatic and van der Waals</div><div>interactions between the inhibitor and 3CLpro. Further, we have identified important residues</div><div>controlling the 3CLpro-ligand binding from per-residue based decomposition of the binding free</div><div>energy. Finally, we have compared ΔGbind of these two inhibitors with the anti-HIV retroviral</div><div>drugs, such as lopinavir and darunavir. It is observed that α-ketoamide is more potent compared</div><div>to both lopinavir and darunavir. In the case of lopinavir, a decrease in the size of the van der</div><div>Waals interactions is responsible for the lower binding affinity compared to α-ketoamide. On</div><div>the other hand, in the case of darunavir, a decrease in the favorable intermolecular electrostatic</div><div>and van der Waals interactions contributes to lower affinity compared to α-ketoamide. Our</div><div>study might help in designing rational anticoronaviral drugs targeting the SARS-CoV-2 main</div><div>protease. </div>