Structure-based development of a subtype-selective orexin 1 receptor antagonist

Hellmann J, Drabek M, Yin J, Gunera J, Pröll T, Kraus F, Langmead CJ, Hübner H, Weikert GD, Kolb P, Rosenbaum DM, Gmeiner P (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Book Volume: 117

Pages Range: 18059-18067

Journal Issue: 30

DOI: 10.1073/pnas.2002704117

Abstract

Orexins are neuropeptides that activate the rhodopsin-like G protein -coupled receptors OX1R and OX2R. The orexin system plays an im-portant role in the regulation of the sleep-wake cycle and the regu-lation of feeding and emotions. The nonselective orexin receptor antagonist suvorexant has been the first drug on the market target-ing the orexin system and is prescribed for the treatment of insomnia. Subtype-selective OX1R antagonists are valuable tools to further in-vestigate the functions and physiological role of the OX1R in vivo and promising lead compounds for the treatment of drug addiction, anx-iety, pain or obesity. Starting from the OX1R and OX2R crystal struc-tures bound to suvorexant, we exploited a single amino acid difference in the orthosteric binding site by using molecular docking and structure-based drug design to optimize ligand interactions with the OX1R while introducing repulsive interactions with the OX2R. A newly established enantiospecific synthesis provided li-gands showing up to 75-fold selectivity for the OX1R over the OX2R subtype. The structure of a new OX1R antagonist with sub-nanomolar affinity (JH112) was determined by crystallography in complex with the OX1R and corresponded closely to the docking -predicted geometry. JH112 exhibits high selectivity over a panel of different GPCRs, is able to cross the blood-brain barrier and acts as slowly diffusing and insurmountable antagonist for Gq protein acti-vation and in particular beta-arrestin-2 recruitment at OX1R. This study demonstrates the potential of structure-based drug design to de-velop more subtype-selective GPCR ligands with potentially reduced side effects and provides an attractive probe molecule and lead compound.

Authors with CRIS profile

Involved external institutions

University of Texas Southwestern Medical Center (UT Southwestern) United States (USA) (US) Philipps-Universität Marburg Germany (DE) Monash University Australia (AU)

How to cite

APA:

Hellmann, J., Drabek, M., Yin, J., Gunera, J., Pröll, T., Kraus, F.,... Gmeiner, P. (2020). Structure-based development of a subtype-selective orexin 1 receptor antagonist. Proceedings of the National Academy of Sciences of the United States of America, 117(30), 18059-18067. https://doi.org/10.1073/pnas.2002704117

MLA:

Hellmann, Jan, et al. "Structure-based development of a subtype-selective orexin 1 receptor antagonist." Proceedings of the National Academy of Sciences of the United States of America 117.30 (2020): 18059-18067.

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