K36-based inhibitor analogs as potential therapeutics against SARS-CoV-2 main protease (Mpro): a computational investigation.

The global pandemic caused by SARS-CoV-2 has underscored the critical necessity for effective antiviral therapies. The viral main protease (Mpro), crucial for viral replication, has emerged as a promising therapeutic target. In the present study, the inhibitory potential of ten drug-like compounds (KL1-KL10), designed as derivatives of the parent inhibitor K36, against Mpro, has been computationally investigated. To elucidate the binding affinities and interactions of the suggested drugs with the Mpro active site, molecular docking and molecular dynamics (MD) simulations till 500 nanoseconds have been applied. Our results revealed that many suggested inhibitors exhibited enhanced binding affinities compared to the parent inhibitor K36. Among these, KL7 displayed the most favourable binding characteristics, with a docking score of -13.54 and MM-PBSA binding energy of -34.57 kJ/mol, surpassing that of K36. Molecular dynamics simulations demonstrated persistent binding of these compounds to Mpro, with RMSD values ranging from 0.5 to 2.0 nm, suggesting their potential as effective inhibitors. These findings suggest that the proposed ligands hold promise as potential scaffolds for developing potent antiviral drugs against COVID-19.