Docking, Molecular Dynamics and MMPBSA Study of Selected FDA-Approved Drugs Against SARS-CoV-2 Proteases and Spike Proteins

Background and objectives: Coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus belongs to the Coronaviridae family, which also includes the viruses responsible for the SARS and MERS outbreaks. The COVID-19 pandemic, which originated in Wuhan, China, has posed significant global health challenges due to the absence of targeted antiviral therapies. In response, drug repurposing has emerged as a practical strategy for identifying effective treatments. In this study, 28 FDA-approved drugs were computationally screened against key SARS-CoV-2 targets, including the papain-like protease, main protease, and spike protein. Methods: The screening involves molecular docking techniques followed by within-pocket optimization and binding energy calculations using the MMGBSA approach. The top ranked drugs were subjected to molecular dynamic simulation and MMPBSA energy calculations. Results: Hydroxychloroquine, rifampicin, ambroxol, chlorpromazine, clarithromycin, ranitidine and ofloxacin provide the best scores against viral proteins according to molecular docking and MMGBSA calculations stage. The top-ranked eleven drugs (with respect to each protein) from the previous step were subjected to molecular dynamics (MD) simulations to assess the stability of ligand–protein interactions and to calculate binding energy using the MMPBSA approach. Conclusions: The viral proteins showed stable complexes with ambroxol, rifampicin, famotidine, ranitidine, oseltamivir, ofloxacin, and ciprofloxacin, which exhibited the most favourable binding energies, suggesting their potential for repurposing as anti-SARS-CoV-2.