Antiviral agents against COVID-19: structure-based design of specific peptidomimetic inhibitors of SARS-CoV-2 main protease

Despite the intense development of vaccines and antiviral therapeutics, no specific treatment of coronavirus disease 2019 (COVID-19), caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently available. Recently, X-ray crystallographic structures of a validated pharmacological target of SARS-CoV-2, the main protease (M(pro) also called 3CL(pro)) in complex with peptide-like irreversible inhibitors have been published. We have carried out computer-aided structure-based design and optimization of peptidomimetic irreversible α-ketoamide M(pro) inhibitors and their analogues using MM, MD and QM/MM methodology, with the goal to propose lead compounds with improved binding affinity to SARS-CoV-2 M(pro), enhanced specificity for pathogenic coronaviruses, decreased peptidic character, and favourable drug-like properties. The best inhibitor candidates designed in this work show largely improved interaction energies towards the M(pro) and enhanced specificity due to 6 additional hydrogen bonds to the active site residues. The presented results on new SARS-CoV-2 M(pro) inhibitors are expected to stimulate further research towards the development of specific anti-COVID-19 drugs.