We discover conformational changes occurring at the active site of 3CLPro caused by the binding of a ligand at an experimentally known allosteric binding site and establish its relation to the inhibitory effect of that ligand. We demonstrate how these changes affect the binding of ligands at the main (active) site by distorting the binding pose. In addition, we also discovered a novel allosteric mechanism of action for a ligand that is hitherto known to act only by binding at the substrate binding site and blocking the catalytic dyad.