The repurposing of FDA-approved drugs to stop viral replication in COVID-19 treatment: a comprehensive molecular docking and dynamics analysis

Abstract

Amidst a public health crisis such as the SARS-CoV-2 induced COVID-19 pandemic, the urgency to develop and provide access to novel drugs becomes paramount. In these scenarios, repurposing existing drugs emerges as an appealing strategy due to their established safety profiles and prior regulatory approvals, potentially streamlining their adoption for new therapeutic purposes. There has been a notable interest in investigating the repurposing potential of FDA-approved drugs to combat the disease triggered by the SARS-CoV-2 virus. This investigation was conducted with the objective of identifying FDA-approved antiviral drugs that could target both the original and mutant forms of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) protein, given the escalating prevalence of SARS-CoV-2 mutations that undermined vaccine efficacy and underscored the need for alternative treatment avenues. Despite ongoing clinical trials, the selection of drugs specifically designed to combat SARS-CoV-2 remains limited. The present study aimed to assess the inhibitory potential of eight approved antiviral drugs. The wild-type and mutant (P323L) RdRp protein (PDB ID: 7BV2). By utilizing molecular docking techniques, the selected drugs were evaluated based on their binding affinities with both the mutant and wild-type RdRp protein. Subsequently, the protein-ligand complexes exhibiting the highest binding affinities were subjected to a 150 ns molecular dynamics simulation to evaluate their stability. The outcomes of the molecular docking analysis pinpointed Dolutegravir and Beclabuvir as possessing the most robust binding affinities for both mutant and wild-type RdRp systems. These findings prompted the selection of these drugs for an in-depth molecular dynamic simulation (MDS) investigation. The comprehensive analysis of Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA) and Secondary Structure Dynamics confirmed that Dolutegravir and Beclabuvir are potent inhibitors of the NSP12 protein. Collectively, the computational assessments put forth two potential contenders: Dolutegravir and Beclabuvir as promising inhibitors against both the wild-type and mutant RdRp proteins. To further validate these drug candidates, rigorous in vitro and in vivo investigations are warranted which could eventually position them as valuable therapeutic agents in the fight against COVID-19.