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

Abstract: The COVID-19 pandemic has initiated a global health emergency, with an exigent need for effective cure. Progressively, drug repurposing is emerging as a promising 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 repurposing 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 affinity. We shortlisted six favorable drugs and examined their physiochemical and pharmacokinetic properties of these top-ranked selected drugs and their best binding interaction for specific target protease 3CLpro. Our study provides an efficient framework for drug repurposing against COVID-19, and establishes the potential of combining molecular docking with machine learning regression approaches to accelerate the identification of potential therapeutic candidates. Our findings contribute to the larger goal of finding effective cures for COVID-19, which is an acute global health challenge. Keywords: COVID-19; main protease 3CL; drug repurposing; QSAR model; binding affinity; molecular docking 1 Introduction The COVID-19 outbreak has presented an unprecedented worldwide health emergency, with over 687 million confirmed cases and over 6.8 million deaths globally as of May 2023 according to https://www.worldometers.info/coronavirus/. At present, there is no certain drug available to treat COVID-19, and the development of effective cures has become a priority for researchers globally [1]. COVID-19 is triggered by SARS-CoV-2, a positive-sense single-stranded RNA virus that mainly infects the respiratory tract of humans [2]. When the spike protein attaches to the ACE2 receptor on the surface of human cells, the virus enters the cell, and then it utilizes the host's cellular machinery to replicate and spread throughout the body. Figure 1 depicts the life cycle of a coronavirus.