Design Of New Inhibitor Compounds Against SARS-COV-2 Main Protease Using Computer-Assisted Retrosynthetic Methods

SARS-CoV-2 is the pathogen that caused the COVID-19 (coronavirus disease 2019) pandemic. While effective vaccines have been developed, there is still an urgent need to develop antiviral drugs for post-infection treatment. This study focuses on the design of novel inhibitory compounds against the SARS-CoV-2 main protease, a key enzyme in viral replication. Reported Mpro inhibitor compounds were fragmented using computer-assisted retrosynthetic methods, and new inhibitors were designed from these fragments following synthesizability rules. The binding affinities of the newly designed compounds were analyzed through docking calculations, and the top 5 compounds showed higher binding affinities than previously described inhibitors, with docking scores ranging from -11.67 to -12.51 kcal/mol. Similarity searches on PubChem revealed that these designed compounds are 83-95% similar to a large number of existing commercially available proprietary compounds, indicating limited novelty but potentially improved synthetic accessibility. This study demonstrates the potential of computer-assisted retrosynthetic design to rapidly generate new, synthetically feasible inhibitor candidates for further optimization and development as SARS-CoV-2 antiviral therapeutics.