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.
