jm6b00333_si_002.csv (53.07 kB)
Pharmacophore Model To Discover OX1 and OX2 Orexin Receptor Ligands
dataset
posted on 2016-08-22, 00:00 authored by Ainoleena Turku, Alexandre Borrel, Teppo O. Leino, Lasse Karhu, Jyrki P. Kukkonen, Henri XhaardSmall
molecule agonists and antagonists of the orexinergic system
have key implications for research and therapeutic purposes. We report
a pharmacophore model trained on ∼200 antagonists and prospectively
validated by screening a collection of ∼137,000 compounds.
The resulting hit list, 395 compounds, was tested for OX1 and OX2 receptor activity using calcium mobilization
assay in recombinant cell lines. Validation was conducted using both
calcium mobilization and [125I]-orexin‑A competition
binding. Compounds 4–7 have weak
agonist activity and Ki’s in the 1–30 μM
range; compounds 8–14 are antagonists
with Ki’s in the 0.1–10 μM range for
OX2 and 1–50 μM for the OX1 receptor.
Docking simulations were used to devise a working hypothesis where
two subpockets are important for activation, one between TM5 and TM6
lined by Phe5.42, Tyr5.47, and Tyr6.48 and another above the orthosteric
pocket lined by Asp2.65 and Tyr7.32.
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pharmacophore model395 compoundsOX 1 receptorantagonistOX 2 Orexin Receptor Ligandscell linesTyr 6.48orexinergic systemDiscover OX 1calcium mobilizationTM 6Docking simulationsagonist activitycalcium mobilization assayPharmacophore ModelTM 5OX 2 receptor activityorthosteric pocketmolecule agonistsOX 1OX 2Asp 2.65
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