It is known that RQN (also known as MUT056399) binds at the substrate binding site of 3CL protease (also known as main protease) and inhibits viral replication by blocking access to the catalytic site consisting of CYS145 and HIS41. In this study, we have uncovered another mechanism of action of RQN when binding to 3CL protease through which it is able to inhibit the catalytic activity of the main protease. This involves binding to a different binding pocket (denoted as A1). Figures S9-S11 display RMSD timeseries of ARG298 for all 12 "long" replicas for all three 3CLPro complexes studied (binding to 93J, RQN and RQN+LZE). There are sections of trajectories in several replicas where the RMSD value shoots up to values as high as 12 Å or more. Interestingly, this behaviour is only observed when RQN is present in the system (that is, we do not see such high RMSD values in any replica of 3CLPro-93J complex). Moreover, in the case of 3CLPro-RQN+LZE system, this behaviour is found exclusively in replicas where LZE does not bind at the binding site B1 (see Figure for details). In other words, LZE binding at site B1 prevents such a large increase in ARG298 RMSD. Below we explain both such behaviours in detail.