Abstract
The efforts towards developing a potential drug against the current global pandemic, COVID-19, have increased in the past few months. Drug development strategies to target the RNA dependent RNA polymerase (RdRP) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are being tried worldwide. The gene encoding this protein, is known to be conserved amongst positive strand RNA viruses. This enables an avenue to repurpose the drugs designed against earlier reported inhibitors of RdRP. One such strong inhibitor is remdesivir which has been used against EBOLA infections. The binding of remdesivir to RdRP of SARS-CoV-2 has been studied using the classical molecular dynamics and ensemble docking approach. A comparative study of the simulations of RdRP in the apo and remdesivir-bound form revealed blocking of the template entry site in the presence of remdesivir. The conformation changes leading to this event were captured through principal component analysis. The conformational and thermodynamic parameters supported the experimental information available on the involvement of crucial arginine, serine and aspartate residues belonging to the conserved motifs in RdRP functioning. The catalytic site comprising of SER 759, ASP 760, and ASP 761 (SDD) was observed to form strong contacts with remdesivir. The significantly strong interactions of these residues with remdesivir may infer the latter's binding similar to the normal nucleotides thereby remaining unidentified by the exonuclease activity of RdRP. The ensemble docking of remdesivir too, comprehended the involvement of similar residues in interaction with the inhibitor. This information on crucial interactions between conserved residues of RdRP with remdesivir through in silico approaches may be useful in designing inhibitors.
Highlights
COVID-19 that emerged as global pandemic is spreading in an uncontrollable manner, in spite of the safety norms and the therapeutics that have been employed to overcome the disease
The work reported in the current paper shows the interactions of remdesivir with the RNA dependent RNA polymerase (RdRP) residues and the changes the enzyme undergoes on binding to this inhibitor through multiple molecular dynamics simulations
It was observed that for the palm subdomain two conformations were populated in terms of the Root Mean Square Deviation (RMSD) values for the RdRP–Apo simulations as compared to one which was observed for the RdRP–RDV simulations
Summary
COVID-19 that emerged as global pandemic is spreading in an uncontrollable manner, in spite of the safety norms and the therapeutics that have been employed to overcome the disease. The ORF1a and ORF1b code for two long polypeptide chains namely, pp1a and pp1b which are cleaved by the viral proteases and lead to the generation of 16 non-structural proteins (nsp).[2,3] These proteins are named as nsp[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16] each of these performing their individual viral functions Amongst these nsp, the nsp[12], is the RNA dependent RNA polymerase (RdRP) which is responsible for viral duplication.[4] Duplication being the primary function for any virus to survive, the gene that codes for this protein are known to be the most conserved.[5,6,7,8,9] Sequence similarity studies suggests that it shows maximum identity with the RdRP of SARS-CoV virus, which was known to affect the humans in and around the year 2003.10 The sequence of SARS-CoV-2 RdRP shares 96.3% similarity with the RdRP of SARS-CoV.[11] Owing to its function, it has been a strong candidate to develop inhibitors against, as blocking this protein would lead to reduction in the spread of the virus.
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