Figure 7.

Ligand binding modes in conserved lipophilic hotspots in orexin receptor crystal structures. Comparison of binding modes of suvorexant (2), filorexant (3), daridorexant (5), GSK1059865 (10), pyridothiadiazinone compound 14, ACT-462206 (15), diazaspirodecane compound 16, lemborexant (4) in OX₁, suvorexant (2), EMPA (8), HTL6641 (13) in OX₂, and EMPA (8) in OX₁ (A127^3.33T mutant). GRID maps are contoured (transparent solid) and colored in the following manner: C1 is the probe (lipophilic) in yellow at −2.8 kcal/mol, and the CH₃ methyl group probe is in gray at 1 kcal/mol, which defines the pocket surface in terms of how close a ligand carbon atom can reside. Positions of residues S103^2.61, W112^23.50, A127^3.33, F219^5.42, Y311^6.48, and Y348^7.43 in OX₁ and of T111^2.61, W120^23.50, T135^3.33, F227^5.42, Y317^6.48, and Y354^7.43 in OX₂ are provided as reference. Whereas direct polar interactions between the chemically diverse ligands and the orexin receptor binding site are limited and not conserved (see Figure 6), all ligands target at least three of the four lipophilic hotspot regions I–IV located between A/T^3.33 and F^5.42 (I), S/T^2.61 and W^23.50 (II), S/T^2.61, Y^6.48 and Y^7.43 (III), and F^5.42 and Y^6.48 (IV).