Riluzole and lamotrigine bind promiscuously in two or three of the fenestrations . (A–E) Fenestration binding mode of riluzole (A and C) and lamotrigine (B and D)—showing free energy surfaces (FES) reproduced from metadynamics simulations (A and B); representative binding pose of each of the top five clusters compared to the pose captured in new cryo-EM structures, PDB IDs 8thg and 8thh (C and D); percentage of the top five clusters where interactions between the drug and protein residues were identified (E). FES contours are shown every 4 kJ/mol.