In silico evaluation of potential intervention against SARS-CoV-2 RNA-dependent RNA polymerase

With few available effective interventions, emergence of novel mutants responding poorly to existing vaccines and ever swelling newer waves of infection, SARS-CoV-2 is posing difficult challenges to mankind. This mandates development of newer and effective therapeutics to prevent loss of life and contain the spread of this deadly virus. Nsp12 or RNA-dependent RNA polymerase (RdRp) is a suitable druggable target as it plays a central role in viral replication.

Catalytically important conserved amino acid residues of RdRp were delineated through a comprehensive literature search and multiple sequence alignments. PDB ID 7BV2 was used to create binding pockets using SeeSAR and to generate docked poses of the FDA approved drugs on the receptor and estimating their binding affinity and other properties.

In silico approach used in this study assisted in prediction of several potential RdRp inhibitors; and re-validation of the already reported ones. Five molecules namely Inosine, Ribavirin, 2-Deoxy-2-Fluoro-D-glucose, Guaifenesin, and Lamivudine were shortlisted which exhibited reasonable binding affinities, with neither torsional nor intermolecular or intramolecular clashes.

This study aimed to widen the prospect of interventions against the SARS-CoV-2 RdRp. Our results also re-validate already reported molecules like 2-Deoxy-D-glucose as a similar molecule 2-deoxy-2-fluoro-D-glucose is picked up in this study. Additionally, ribavirin and lamivudine, already known antivirals with polymerase inhibition activity are also picked up as the top leads. Selected potent inhibitors of RdRp hold promise to cater for any future coronavirus-outbreak subject to in vitro and in vivo validations.