Structure-Based Design of a Chemical Probe Set for the 5‑HT5A Serotonin Receptor
datasetposted on 2022-02-23, 16:36 authored 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. Shoichet
The 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.
Read the peer-reviewed publication
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