Our research team has published a new study focused on the main protease (Mpro) of SARS-CoV-2, a key enzyme essential for coronavirus replication. As part of the recently completed LEAD GAČR project, we employed high-throughput crystallographic screening of a large collection of small molecules and identified a novel pyrazolo[1,5-a]pyrimidine ligand binding within the active site of the protease. Subsequent structural analysis enabled detailed characterization of interactions within the individual binding subsites of the enzyme (S1/S2) and provided a basis for the rational design of new analogues with improved affinity toward the viral protein.
The study was carried out in collaboration with the Macromolecular Crystallography group at Helmholtz-Zentrum Berlin and the Medical University of Innsbruck. The project combined protein biochemistry, X-ray crystallography, small-molecule design, biophysical methods, and computational modeling of molecular interactions. The findings contribute to a deeper understanding of ligand recognition in coronavirus proteases and demonstrate how experimental and computational approaches can be integrated for the rational development of new bioactive compounds.
Int J Biol Macromol. 2026 May 12:152401.
https://doi.org/10.1016/j.ijbiomac.2026.152401