A new glimpse on the active site of SARS-CoV-2 3CLpro, coupled with drug repurposing study.

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by novel severe acute respiratory syndrome coronavirus (SARS-CoV-2). Its main protease, 3C-like protease (3CLpro), is an attractive target for drug design, due to its importance in virus replication. The analysis of the radial distribution function of 159 3CLpro structures reveals a high similarity index. A study of the catalytic pocket of 3CLpro with bound inhibitors reveals that the influence of the inhibitors is local, perturbing dominantly only residues in the active pocket. A machine learning based model with high predictive ability against SARS-CoV-2 3CLpro is designed and validated. The model is used to perform a drug-repurposing study, with the main aim to identify existing drugs with the highest 3CLpro inhibition power. Among antiviral agents, lopinavir, idoxuridine, paritaprevir, and favipiravir showed the highest inhibition potential. Enzyme - ligand interactions as a key ingredient for successful drug design.