De Novo Drug Design of Potential Inhibitors of SARS-CoV-2 Papain-like Protease

: Here, potential inhibitors of the SARS-CoV-2 papain-like protease (PL pro ) are reported. A drug molecule (PL pro -50), designed de novo using generative neural networks, interacts with PL pro via hydrogen bonding, forming a salt bridge, and π – π stacking, making it a promising drug against PL pro . PL pro -50 has an excellent ADMET profile with good absorbability, high clearance, and low toxicity. Molecular dynamics analysis revealed the stability of the receptor–ligand complex of PL pro -50 and PL pro . An organic retrosynthesis study showed the feasibility of PL pro -50 to be synthesized using low-cost starting materials. Further studies should be performed to determine whether the determined drug candidates are efficacious in treating COVID-19 infections.