Water analysis. The analysis was conducted using an in-house python (v 3.10.6) 56 script with the packages MDtraj (v 1.9.7) 57 and alphashape (v 1.3.1) . We investigated the change of number of water molecules within the region around the binding pocket S1 during MD simulations. This region was defined by a convex hull bordered by the alpha carbon atoms (CA) of residues VAL114, ALA116, GLY138, PHE140, ASN142, GLY146, HIS164, HIS172, GLY174, the carbonyl carbon atom of residue Thr135, and the carbonyl oxygen of residue CYS117. The analysis was performed on 5000 frames of 500-ns MD trajectory for each system.