Structural insights into the binding mode of the hypnotic drug vornorexant to orexin receptors
Year: 2026
Type: article
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 (OX 2 R) and a docking simulation of the drug with orexin type 1 receptor (OX 1 R). The crystal structure of the OX 2 R–vornorexant complex revealed a conserved U-shaped conformation stabilized by hydrophobic and hydrogen-bonding interactions, including key contacts with Asn324, His350 and Pro131. OX 1 R–vornorexant docking simulations indicated a similar binding mode to OX 1 R, 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.
Authors: Masashi Mima, Chiemi Mishima-Tsumagari, Mayumi Sakata-Sakuta, Ryo Iwaoka, Kunihiko Iwamoto
Institution: Taisho Pharmaceutical (Japan)
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,520
OpenAlex ID: W7158878141
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