Inhibition of the RNA-dependent RNA Polymerase of the SARS-CoV-2 by Short Peptide Inhibitors.

The rapid proliferation of SARS-CoV-2 in COVID-19 patients has become detrimental to their lives. However, blocking the replication cycle of SARS-CoV-2 will help in suppressing the viral loads in patients, which would ultimately help in the early recovery. To discover such drugs, molecular docking, MD-simulations, and MM/GBSA approaches have been used herein to examine the role of several short ionic peptides in inhibiting the RNA binding site of the RNA-dependent RNA polymerase (RdRp). Out of the 49 tri- and tetrapeptide inhibitors studied, 8 inhibitors were found to bind RdRp strongly as revealed by the docking studies. Among these inhibitors, the Ala1-Arg2-Lys3-Asp4 and Ala1-Lys2-Lys3-Asp4 are found to make the most stable complexes with RdRp and possess the ΔGbind of -17.41 and -14.21 kcal/mol respectively as revealed by the MD and MM/GBSA studies. Hence these peptide inhibitors would be highly potent in inhibiting the activities of RdRp. It is further found that these inhibitors can occupy the positions of the nucleotide triphosphate (NTP) insertion site, thereby inhibiting the replication of the viral genome by obstructing the synthesis of new nucleotides. Structural and energetic comparisons of these inhibitors with Remdesivir and similar nucleotide drugs show that these peptides would be more specific and hence may act as promiscuous antiviral agents against RdRp.

Artificially expanded genetic information systems (AEGISs) as potent inhibitors of the RNA-dependent RNA polymerase of the SARS-CoV-2.

The recent outbreak of the SARS-CoV-2 infection has affected the lives and economy of more than 200 countries. The unavailability of virus-specific drugs has created an opportunity to identify potential therapeutic agents that can control the rapid transmission of this pandemic. Here, the mechanisms of the inhibition of the RNA-dependent RNA polymerase (RdRp), responsible for the replication of the virus in host cells, are examined by different ligands, such as Remdesivir (RDV), Remdesivir monophosphate (RMP), and several artificially expanded genetic information systems (AEGISs) including their different sequences by employing molecular docking, MD simulations, and MM/GBSA techniques. It is found that the binding of RDV to RdRp may block the RNA binding site. However, RMP would acquire a partially flipped conformation and may allow the viral RNA to enter into the binding site. The internal dynamics of RNA and RdRp may help RMP to regain its original position, where it may inhibit the RNA-chain elongation reaction. Remarkably, AEGISs are found to obstruct the binding site of RNA. It is shown that dPdZ, a two-nucleotide sequence containing P and Z would bind to RdRp very strongly and may occupy the positions of two nucleotides in the RNA strand, thereby denying access of the substrate-binding site to the viral RNA. Thus, it is proposed that the AEGISs may act as novel therapeutic candidates against the SARS-CoV-2. However, in vivo evaluations of their potencies and toxicities are needed before using them against COVID-19.Communicated by Ramaswamy H. Sarma.

Peptide-like and small-molecule inhibitors against Covid-19.

Coronavirus disease strain (SARS-CoV-2) was discovered in 2019, and it is spreading very fast around the world causing the disease Covid-19. Currently, more than 1.6 million individuals are infected, and several thousand are dead across the globe because of Covid-19. Here, we utilized the in-silico approaches to identify possible protease inhibitors against SARS-CoV-2. Potential compounds were screened from the CHEMBL database, ZINC database, FDA approved drugs and molecules under clinical trials. Our study is based on 6Y2F and 6W63 co-crystallized structures available in the protein data bank (PDB). Seven hundred compounds from ZINC/CHEMBL databases and fourteen hundred compounds from drug-bank were selected based on positive interactions with the reported binding site. All the selected compounds were subjected to standard-precision (SP) and extra-precision (XP) mode of docking. Generated docked poses were carefully visualized for known interactions within the binding site. Molecular mechanics-generalized born surface area (MM-GBSA) calculations were performed to screen the best compounds based on docking scores and binding energy values. Molecular dynamics (MD) simulations were carried out on four selected compounds from the CHEMBL database to validate the stability and interactions. MD simulations were also performed on the PDB structure 6YF2F to understand the differences between screened molecules and co-crystallized ligand. We screened 300 potential compounds from various databases, and 66 potential compounds from FDA approved drugs. Cobicistat, ritonavir, lopinavir, and darunavir are in the top screened molecules from FDA approved drugs. The screened drugs and molecules may be helpful in fighting with SARS-CoV-2 after further studies.Communicated by Ramaswamy H. Sarma.