Drug Repurposing Targeting COVID-19 3CL Protease using Molecular Docking and Machine Learning Regression Approach

The COVID-19 pandemic has initiated a global health emergency, with an exigent need for effective cure. Progressively, drug repurposing is emerging a promise solution as it saves the time, cost and labor. However, the number of drug candidates that have been identified as being repurposed for the treatment of COVID-19 are still insufficient, so more effective and thorough drug exploring strategies are required. In this study, we joint the molecular docking with machine learning regression approaches to find some prospective therapeutic candidates for COVID-19 treatment. We screened the 5903 approved drugs for their inhibition by targeting the main protease 3CL of SARS-CoV-2, which is responsible to replicate the virus. Molecular docking is used to calculate the binding affinities of these drugs to the main protease 3CL. We employed several machine learning regression approaches for QSAR modeling to find out some potential drugs with high binding affinities. Our outcomes demonstrated that the Decision Tree Regression (DTR) model with best scores of R2 and RMSE, is the most suitable model to explore the potential drugs. We shortlisted six favorable drugs. These drugs have novel repurposing potential, except for one antiviral ZINC203757351 compound that has already been identified in other studies. We further examined the physiochemical and pharmacokinetic properties of these most potent drugs and their best binding interaction to specific target protease 3CLpro. Our verdicts contribute to the larger goal of finding effective cures for COVID-19, which is an acute global health challenge. The outcomes of our study provide valuable insights into potential therapeutic candidates for COVID-19 treatment.