Discovering potential inhibitors against SARS-CoV-2 by targeting Nsp13 Helicase

Abstract

The rise in the incidence of COVID-19 as a result of SARS-CoV-2 infection has threatened public health globally. Till now, there have been no proper prophylactics available to fight COVID-19, necessitating the advancement and evolution of effective curative against SARS-CoV-2. This study aimed at the nonstructural protein 13 (nsp13) helicase as a promising target for drug development against COVID-19. A unique collection of nucleoside analogs was screened against the SARS-CoV-2 helicase protein, for which a molecular docking experiment was executed to depict the selected ligand’s binding affinity with the SARS-CoV-2 helicase proteins. Simultaneously, molecular dynamic simulations were performed to examine the protein’s binding site’s conformational stability, flexibility, and interaction with the ligands. Key nucleoside ligands were selected for pharmacokinetic analysis based on their docking scores. Selected ligands (cordycepin and pritelivir) showed excellent pharmacokinetics and were well stabilized at the proteins’ binding site throughout the MD simulation. We have also performed binding free energy analysis or the binding characteristics of ligands with Nsp13 by using MM-PBSA and MM-GBSA. Free energy calculation by MM-PBSA and MM-GBSA analysis suggests that pritelivir may work as viable therapeutics for efficient drug advancement against SARS-CoV-2 Nsp13 helicase, potentially arresting the SARS-CoV-2 replication.

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV-2
• nsp13
• helicase
• molecular docking
• ADMET
• simulation and free energy

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The lab is supported by the Science and Engineering Research Board, India (FILE NO. ECR/2015//000155) and the Department of Biotechnology (India) (order no: BT/PR16224/NER/95/176/2015 & BT/PR24504/NER/95/746/2017) to Dr. Diwakar Kumar. Deep Bhowmik received funding from the SERB grant (FILE NO. ECR/2015//000155). Rajat Nandi received funding from the DBT grant (order no: BT/PR24504/NER/95/746/2017).