Structure-Based Design of a Chemical Probe Set for the 5-HT Serotonin Receptor

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Feb 23

PMID 35195401

Authors

Anat Levit Kaplan

Ryan T Strachan

Joao M Braz

Veronica Craik

Samuel Slocum

Thomas Mangano

Vanessa Amabo

Henry ODonnell

Parnian Lak

Allan I Basbaum

Bryan L Roth

Brian K Shoichet

Affiliations

Soon will be listed here.

Abstract

The 5-HT receptor (5-HTR), 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-HTR 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-HTR homology model identified 5 mid-μM ligands, one of which was optimized to , a 42 nM arrestin-biased partial agonist at the 5-HTR with a more restricted off-target profile and decreased assay liabilities versus SB-699551. Site-directed mutagenesis supported the docked pose of . Surprisingly, analogs of that lost the 5-HTR activity revealed that 5-HTR engagement is nonessential for alleviating pain, contrary to studies with less-selective ligands. and analogs constitute a selective probe set with which to study the function of the 5-HTR.

Citing Articles

Uncovering the unique characteristics of different groups of 5-HTR ligands with reference to their interaction with the target protein.

Kordylewski S, Bugno R, Bojarski A, Podlewska S Pharmacol Rep. 2024; 76(5):1130-1146.

PMID: 38971919 PMC: 11387456. DOI: 10.1007/s43440-024-00622-4.

Exploration of prognostic and treatment markers in hepatocellular carcinoma via GPCR-related genes analysis.

Wang Y, Jin B, Wu X, Xing J, Zhang B, Chen X Heliyon. 2024; 10(9):e29659.

PMID: 38694033 PMC: 11058304. DOI: 10.1016/j.heliyon.2024.e29659.

SerotoninAI: Serotonergic System Focused, Artificial Intelligence-Based Application for Drug Discovery.

Lapinska N, Paclawski A, Szlek J, Mendyk A J Chem Inf Model. 2024; 64(7):2150-2157.

PMID: 38289046 PMC: 11005036. DOI: 10.1021/acs.jcim.3c01517.

Structural studies of serotonin receptor family.

Parajulee A, Kim K BMB Rep. 2023; 56(10):527-536.

PMID: 37817438 PMC: 10618075.

Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors.

Fink E, Bardine C, Gahbauer S, Singh I, Detomasi T, White K Protein Sci. 2023; 32(8):e4712.

PMID: 37354015 PMC: 10364469. DOI: 10.1002/pro.4712.

References

Wercberger R, Braz J, Weinrich J, Basbaum A . Pain and itch processing by subpopulations of molecularly diverse spinal and trigeminal projection neurons. Proc Natl Acad Sci U S A. 2021; 118(28). PMC: 8285968. DOI: 10.1073/pnas.2105732118. View

Mysinger M, Shoichet B . Rapid context-dependent ligand desolvation in molecular docking. J Chem Inf Model. 2010; 50(9):1561-73. DOI: 10.1021/ci100214a. View

McCorvy J, Roth B . Structure and function of serotonin G protein-coupled receptors. Pharmacol Ther. 2015; 150:129-42. PMC: 4414735. DOI: 10.1016/j.pharmthera.2015.01.009. View

Dogrul A, Seyrek M, Akgul E, Cayci T, Kahraman S, Bolay H . Systemic paracetamol-induced analgesic and antihyperalgesic effects through activation of descending serotonergic pathways involving spinal 5-HT₇ receptors. Eur J Pharmacol. 2011; 677(1-3):93-101. DOI: 10.1016/j.ejphar.2011.12.016. View

Hauser A, Attwood M, Rask-Andersen M, Schioth H, Gloriam D . Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov. 2017; 16(12):829-842. PMC: 6882681. DOI: 10.1038/nrd.2017.178. View

Lansu K, Karpiak J, Liu J, Huang X, McCorvy J, Kroeze W . In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat Chem Biol. 2017; 13(5):529-536. PMC: 5391270. DOI: 10.1038/nchembio.2334. View

Kassai F, Schlumberger C, Kedves R, Pietraszek M, Jatzke C, Lendvai B . Effect of 5-HT5A antagonists in animal models of schizophrenia, anxiety and depression. Behav Pharmacol. 2012; 23(4):397-406. DOI: 10.1097/FBP.0b013e3283565248. View

Word J, Lovell S, Richardson J, Richardson D . Asparagine and glutamine: using hydrogen atom contacts in the choice of side-chain amide orientation. J Mol Biol. 1999; 285(4):1735-47. DOI: 10.1006/jmbi.1998.2401. View

Jordan M, Schallhorn A, Wurm F . Transfecting mammalian cells: optimization of critical parameters affecting calcium-phosphate precipitate formation. Nucleic Acids Res. 1996; 24(4):596-601. PMC: 145683. DOI: 10.1093/nar/24.4.596. View

10.

Keiser M, Setola V, Irwin J, Laggner C, Abbas A, Hufeisen S . Predicting new molecular targets for known drugs. Nature. 2009; 462(7270):175-81. PMC: 2784146. DOI: 10.1038/nature08506. View

11.

Alhaider A, Wilcox G . Differential roles of 5-hydroxytryptamine1A and 5-hydroxytryptamine1B receptor subtypes in modulating spinal nociceptive transmission in mice. J Pharmacol Exp Ther. 1993; 265(1):378-85. View

12.

Shields S, Eckert 3rd W, Basbaum A . Spared nerve injury model of neuropathic pain in the mouse: a behavioral and anatomic analysis. J Pain. 2003; 4(8):465-70. DOI: 10.1067/s1526-5900(03)00781-8. View

13.

Haring M, Zeisel A, Hochgerner H, Rinwa P, Jakobsson J, Lonnerberg P . Neuronal atlas of the dorsal horn defines its architecture and links sensory input to transcriptional cell types. Nat Neurosci. 2018; 21(6):869-880. DOI: 10.1038/s41593-018-0141-1. View

14.

Rees S, den Daas I, Foord S, Goodson S, Bull D, Kilpatrick G . Cloning and characterisation of the human 5-HT5A serotonin receptor. FEBS Lett. 1994; 355(3):242-6. DOI: 10.1016/0014-5793(94)01209-1. View

15.

Wacker D, Wang S, McCorvy J, Betz R, Venkatakrishnan A, Levit A . Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell. 2017; 168(3):377-389.e12. PMC: 5289311. DOI: 10.1016/j.cell.2016.12.033. View

16.

Zhang Y, Yang Z, Gao X, Wu G . The role of 5-hydroxytryptamine1A and 5-hydroxytryptamine1B receptors in modulating spinal nociceptive transmission in normal and carrageenan-injected rats. Pain. 2001; 92(1-2):201-11. DOI: 10.1016/s0304-3959(01)00259-7. View

17.

Thorne N, Shen M, Lea W, Simeonov A, Lovell S, Auld D . Firefly luciferase in chemical biology: a compendium of inhibitors, mechanistic evaluation of chemotypes, and suggested use as a reporter. Chem Biol. 2012; 19(8):1060-72. PMC: 3449281. DOI: 10.1016/j.chembiol.2012.07.015. View

18.

Corbett D, Heightman T, Moss S, Bromidge S, Coggon S, Longley M . Discovery of a potent and selective 5-ht5A receptor antagonist by high-throughput chemistry. Bioorg Med Chem Lett. 2005; 15(18):4014-8. DOI: 10.1016/j.bmcl.2005.06.024. View

19.

Mysinger M, Carchia M, Irwin J, Shoichet B . Directory of useful decoys, enhanced (DUD-E): better ligands and decoys for better benchmarking. J Med Chem. 2012; 55(14):6582-94. PMC: 3405771. DOI: 10.1021/jm300687e. View

20.

Wang C, Jiang Y, Ma J, Wu H, Wacker D, Katritch V . Structural basis for molecular recognition at serotonin receptors. Science. 2013; 340(6132):610-4. PMC: 3644373. DOI: 10.1126/science.1232807. View