This P-loop acts as a one gate-keeper structure of PL-pro inhibitors, having a dynamic motion from opened to closed conformation upon ligand binding. Recent studies by Ismail et al, revealed that upon applying 1 μs of classical molecular dynamics simulation to the PL-pro apo-form, the P-loop shows a high degree of flexibility, as shown in (Figure ). This creates a critical challenge in the discovery and optimization of new hit compounds against such highly flexible binding sites.