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 also called 3CL) 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 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, enhanced specificity for pathogenic coronaviruses, decreased peptidic character, and favourable drug-like properties.