Identification of Promising Sulfonamide Chalcones as Inhibitors of SARS-CoV-2 3CLpro through Structure-Based Virtual Screening and Experimental Approaches

3CL(pro) is a viable target for developing antiviraltherapiesagainst the coronavirus. With the urgent need to find new possibleinhibitors, a structure-based virtual screening approach was developed.This study recognized 75 pharmacologically bioactive compounds fromour in-house library of 1052 natural product-based compounds thatsatisfied drug-likeness criteria and exhibited good bioavailabilityand membrane permeability. Among these compounds, three promisingsulfonamide chalcones were identified by combined theoretical andexperimental approaches, with SWC423 being the most suitable representativecompound due to its competitive inhibition and low cytotoxicity inVero E6 cells (EC50 = 0.89 & PLUSMN; 0.32 & mu;M; CC50 = 25.54 & PLUSMN; 1.38 & mu;M; SI = 28.70). The binding andstability of SWC423 in the 3CL(pro) active site were investigatedthrough all-atom molecular dynamics simulation and fragment molecularorbital calculation, indicating its potential as a 3CL(pro) inhibitor for further SARS-CoV-2 therapeutic research. These findingssuggested that inhibiting 3CL(pro) with a sulfonamide chalconesuch as SWC423 may pave the effective way for developing COVID-19treatments.