Drug repurposing studies targeting SARS-CoV-2: an ensemble docking approach on drug target 3C-like protease (3CLpro)

The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome - novel Coronavirus 2 (SARS-CoV-2). SARS-CoV-2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-2003. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-CoV-2. The high-resolution crystal structure of the main protease of SARS-CoV-2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 mu s open-source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for the main protease helped in exploring the conformational variation in the drug-binding site of the main protease leading to the efficient binding of more relevant drug molecules. The drugs obtained as top hits from the ensemble docking possessed anti-bacterial and anti-viral properties. Thisin silicoensemble docking approach would support the identification of potential candidates for repurposing against COVID-19. Communicated by Ramaswamy H. Sarma

Automated summary

The COVID-19 pandemic caused numerous deaths worldwide, with the causative agent being SARS-CoV-2 and its main protease as a key therapeutic target. Drug repurposing may be effective in targeting this virus, and simulation and structural analysis can help in identifying relevant drug molecules for binding to the main protease of SARS-CoV-2.