Structural insights into the binding mode of the hypnotic drug vornorexant to orexin receptors.

Abstract

Insomnia is a widespread sleep disorder that significantly impairs quality of life and imposes a societal burden. Although benzodiazepines and Z-drugs are commonly used for treating insomnia, these drugs often have side effects, such as excessive muscle relaxation and dependency. The orexin signaling pathway has emerged as a promising therapeutic target for insomnia, with dual orexin receptor antagonists (DORAs) offering an alternative approach to treatment. To reduce the potential of these drugs for next-day residual effects, we developed vornorexant, a novel DORA with a high receptor affinity and a short elimination half-life. In this study, we investigated the molecular interactions of this drug with human orexin receptors through crystal structure analysis of its binding to orexin type 2 receptor (OX₂R) and a docking simulation of the drug with orexin type 1 receptor (OX₁R). The crystal structure of the OX₂R-vornorexant complex revealed a conserved U-shaped conformation stabilized by hydrophobic and hydrogen-bonding interactions, including key contacts with Asn324, His350 and Pro131. OX₁R-vornorexant docking simulations indicated a similar binding mode to OX₁R, with no steric hindrance observed, supporting a balanced dual antagonism. These results provide a structural basis for the high-affinity dual antagonism of vornorexant and offer insights for the design of orexin receptor antagonists.