Unveiling the binding mechanism of orexin 2 receptor antagonists with computational chemistry

A detailed understanding of ligand recognition and binding at the orexin receptor 2 (OXR2) is essential for the rational design of selective therapeutics for sleep and neuropsychiatric disorders. In this study, we investigated the molecular interactions of three dual orexin receptor antagonists (daridorexant, lemborexant, suvorexant) and the selective OXR2 antagonist seltorexant using an integrated computational approach that combined classical molecular docking, explicit-membrane molecular dynamics (MD) simulations of 700 ns, and quantum-based molecular fractionation with conjugate caps (MFCC) calculations coupled with density functional theory (DFT) at the B97D/6-311+G(d,p) level. The ligands exhibited distinct binding profiles, with stabilization mediated by complementary hydrogen bonding, hydrophobic contacts, and aromatic interactions. Daridorexant showed the strongest adaptability and overall binding affinity, while seltorexant displayed a unique pattern of stabilization within a hydrophobic subpocket of the receptor. These findings shed light on the structural and energetic factors that determine OXR2-ligand recognition. The results provide a solid molecular framework for the rational optimization of orexin receptor antagonists with enhanced selectivity and improved pharmacological profiles.