Figure 6.

Interaction analysis and water-mediated hydrogen bond networks in antagonist-bound OX₁ and OX₂ structures. (a) Polar interaction networks of suvorexant (2), filorexant (3), daridorexant (5), GSK1059865 (10), HTL6641 (13), pyridothiadiazinone compound 14, ACT-462206 (15), diazaspirodecane compound 16, lemborexant (4), EMPA (8), SB-334867 (11), and SB-408124 (12) in OX₁, and OX₂ crystal structures. Direct receptor–ligand hydrogen bond interactions, water–ligand interactions, and water–receptor hydrogen bond interactions are indicated by dashed red, blue, and gray lines, respectively. Residues and water molecules involved in hydrogen bond interactions are labeled in black, and residues involved in water-mediated interactions are labeled in gray. Water molecules involved in hydrogen bond interactions with ligands are located in four regions: (1) hydrogen bonded to H^7.39 (Wat 1.1) and/or N^6.55 (Wat 1.2); (2) hydrogen bonded to E^45.52 (Wat 2.2) and/or close to ECL2 (Wat 2.1); (3) hydrogen bonded to Q^3.32 (Wat 3.2) and/or deep in the binding pocket between TMs 2, 3, and 7 (Wat 3.1); (4) between TMs 5 and 6 (Wat 4). (b) Structural receptor–ligand and water–ligand interaction patterns in different OX₁ and OX₂ crystal structures, discriminating non-polar contacts (light gray), aromatic interactions (dark gray), and hydrogen bond interactions with receptor residues (red) and water molecules (blue). Water molecules are annotated as defined in panel (a). (c) Atoms in the chemical structures of the ligands depicted in panel (a) that only form direct hydrogen bond interactions with the receptor, only form water-mediated hydrogen interactions, or form hydrogen bond interactions with both the receptor and water molecules are colored red, blue, and magenta, respectively.