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PDBsum entry 6v9s
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Signaling protein
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PDB id
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6v9s
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References listed in PDB file
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Key reference
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Title
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Structure-Based development of a subtype-Selective orexin 1 receptor antagonist.
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Authors
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J.Hellmann,
M.Drabek,
J.Yin,
J.Gunera,
T.Pröll,
F.Kraus,
C.J.Langmead,
H.Hübner,
D.Weikert,
P.Kolb,
D.M.Rosenbaum,
P.Gmeiner.
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Ref.
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Proc Natl Acad Sci U S A, 2020,
117,
18059-18067.
[DOI no: ]
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PubMed id
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Abstract
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Orexins are neuropeptides that activate the rhodopsin-like G protein-coupled
receptors OX1R and OX2R. The orexin system plays an important role in the
regulation of the sleep-wake cycle and the regulation of feeding and emotions.
The nonselective orexin receptor antagonist suvorexant has been the first drug
on the market targeting the orexin system and is prescribed for the treatment of
insomnia. Subtype-selective OX1R antagonists are valuable tools to further
investigate the functions and physiological role of the OX1R in vivo and
promising lead compounds for the treatment of drug addiction, anxiety, pain or
obesity. Starting from the OX1R and OX2R crystal structures 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 ligands showing up
to 75-fold selectivity for the OX1R over the OX2R subtype. The structure of a
new OX1R antagonist with subnanomolar 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 activation and
in particular β-arrestin-2 recruitment at OX1R. This study demonstrates the
potential of structure-based drug design to develop more subtype-selective GPCR
ligands with potentially reduced side effects and provides an attractive probe
molecule and lead compound.
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