Repurposed drug molecules targeting NSP12 protein of SARS-CoV-2: An in-silico study

Abstract

<abstract> <p>The emergence of SARS-CoV-2 created a havoc worldwide, causing high morbidity, serious complications and mortality. The ORF1ab of SARS-CoV-2 has 16 non-structural proteins which are required for genome replication and transcription. All of these are druggable targets, of which NSP12 (RNA-dependent RNA polymerase), was selected as a potential target for drug molecules. Remdesivir is a recommended drug for SARS-CoV-2 and it targets the RdRp protein. Although Remdesivir was given to COVID-19 patients based on their clinical manifestations, yet the transmission and spread of the virus continued and to add to its pandemicity, new variants emerged from time to time. This necessitates the need for molecular modification of existing antiviral drugs so that more precise targets for halting viral replication can be selected. For this, the approach used was repurposing of the existing drugs. In the present study, ten FDA-approved drugs were chosen on the basis of their properties of inhibiting the RdRp protein. These drugs were subjected for checking the docking score with the target protein. Of these, Remdesivir, Ribavirin, Favipiravir and Baloxavir were taken for further analysis on the basis of their best scores. These drugs were then modified to check the efficiency to inhibit the RdRp and to stop the replication rate of the virus. We docked the modified drugs with the macrodomain of RdRp by using the CB-Dock web server and checked the binding affinity and amino acid contact residues. The modified drugs were also checked for bioactivity in the Molinspiration cheminformatics online tool. Our results showed increased affinity for RdRp of SARS-CoV-2 when compared to the original compound. We also checked the synthetic accessibility of the drugs using the SwissADME tool. The study showed promising results when modified. The findings reported need further confirmation through wet lab studies.</p> </abstract>