Binding properties of selective inhibitors of P323L mutated RdRp of SARS-CoV-2: a combined molecular screening, docking and dynamics simulation study

Abstract

Since 2019 the SARS-CoV-2 and its variants caused COVID-19, such incidents brought the world in pandemic situation. This happened due to furious mutations in SARS-CoV-2, in which some variants had high transmissibility and infective, this led the virus emerged as virulent and worsened the COVID-19 situation. Among the variants, P323L is one of the important mutants of RdRp in SARS-CoV-2. To inhibit the erroneous function of this mutated RdRp, we have screened 943 molecules against the P323L mutated RdRp with the criteria that the molecules with 90% similar to the structure of remdesivir (control drug) resulted nine molecules. Further, these molecules were evaluated by induced fit docking (IFD) identified two molecules (M2 & M4) which are forming strong intermolecular interactions with the key residues of mutated RdRp and has high binding affinity. Docking score of the M2 and M4 molecules with mutated RdRp are −9.24 and −11.87 kcal/mol, respectively. Further, to understand the intermolecular interactions, conformational stability, the molecular dynamics simulation and binding free energy calculations were performed. The binding free energy values of M2 and M4 molecules with the P323L mutated RdRp complexes are −81.60 and −83.07 kcal/mol, respectively. The results of this in silico study confirm that M4 is a potential molecule; hence, it may be considered as the potential inhibitor of P323L mutated RdRp to treat COVID-19 after clinical investigation.

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV-2
• RdRp
• mutant P323L
• remdesivir
• MD simulation

Acknowledgement

The authors thank the Computer Centre, Periyar University for providing the High Performance Cluster (HPC) Computing facility funded by RUSA to perform the MD simulation study reported here.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not for profit sectors.