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Download fileStructure-Based Design of a Chemical Probe Set for the 5‑HT5A Serotonin Receptor
dataset
posted on 23.02.2022, 16:36 by Anat Levit Kaplan, Ryan T. Strachan, Joao M. Braz, Veronica Craik, Samuel Slocum, Thomas Mangano, Vanessa Amabo, Henry O’Donnell, Parnian Lak, Allan I. Basbaum, Bryan L. Roth, Brian K. ShoichetThe
5-HT5A receptor (5-HT5AR), for which
no selective agonists and a few antagonists exist, remains the least
understood serotonin receptor. A single commercial antagonist, SB-699551,
has been widely used to investigate the 5-HT5AR function
in neurological disorders, including pain, but this molecule has substantial
liabilities as a chemical probe. Accordingly, we sought to develop
an internally controlled probe set. Docking over 6 million molecules
against a 5-HT5AR homology model identified 5 mid-μM
ligands, one of which was optimized to UCSF678, a 42
nM arrestin-biased partial agonist at the 5-HT5AR with
a more restricted off-target profile and decreased assay liabilities
versus SB-699551. Site-directed mutagenesis supported the docked pose
of UCSF678. Surprisingly, analogs of UCSF678 that lost the 5-HT5AR activity revealed that 5-HT5AR engagement is nonessential for alleviating pain, contrary
to studies with less-selective ligands. UCSF678 and analogs
constitute a selective probe set with which to study the function
of the 5-HT5AR.
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single commercial antagonistdirected mutagenesis supportedbiased partial agonist6 million molecules42 nm arrestinchemical probe setucsf678 </ bselective probe setr activity revealed5a </ sub5 ‑ htchemical probeselective ligandsselective agonistsμm ligandswidely usedtarget profilesubstantial liabilitiesr engagementr ),neurological disordersincluding paindocked posebased designantagonists existalleviating pain