Structure-based discovery of conformationally selective inhibitors of the serotonin transporter.

ObservationalPubMedMay 16, 2023PMID: 37137306 DOI

Abstract

The serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors target the outward-open state except ibogaine, which has unusual anti-depressant and substance-withdrawal effects, and stabilizes the inward-open conformation. Unfortunately, ibogaine's promiscuity and cardiotoxicity limit the understanding of inward-open state ligands. We docked over 200 million small molecules against the inward-open state of the SERT. Thirty-six top-ranking compounds were synthesized, and thirteen inhibited; further structure-based optimization led to the selection of two potent (low nanomolar) inhibitors. These stabilized an outward-closed state of the SERT with little activity against common off-targets. A cryo-EM structure of one of these bound to the SERT confirmed the predicted geometry. In mouse behavioral assays, both compounds had anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold better than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects.

Authors (21)

Isha SinghLeadDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Suite 508D, San Francisco, CA 94143, USA.

Anubha SethDepartment of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066, USA.

Christian B BillesbølleDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Suite 508D, San Francisco, CA 94143, USA.

Joao BrazDepartment of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.

Ramona M RodriguizDepartment of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC 27710, USA.

Kasturi RoyDepartment of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066, USA.

Bethlehem BekeleDepartment of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066, USA.

Veronica CraikDepartment of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.

Xi-Ping HuangDepartment of Pharmacology, NIMH Psychoactive Drug Screening Program, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Danila BoytsovInstitute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.

Vladimir M PogorelovDepartment of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.

Parnian LakDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Suite 508D, San Francisco, CA 94143, USA.

Henry O'DonnellDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Suite 508D, San Francisco, CA 94143, USA.

Walter SandtnerInstitute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.

John J IrwinDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Suite 508D, San Francisco, CA 94143, USA.

Bryan L RothDepartment of Pharmacology, NIMH Psychoactive Drug Screening Program, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Allan I BasbaumDepartment of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: allan.basbaum@ucsf.edu.

William C WetselDepartment of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC 27710, USA; Departments of Cell Biology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: william.wetsel@duke.edu.

Aashish ManglikDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Suite 508D, San Francisco, CA 94143, USA; Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94115, USA. Electronic address: aashish.manglik@ucsf.edu.

Brian K ShoichetDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Suite 508D, San Francisco, CA 94143, USA. Electronic address: bshoichet@gmail.com.

Gary RudnickDepartment of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066, USA. Electronic address: gary.rudnick@yale.edu.

MeSH Terms

AnimalsMiceFluoxetineIbogaineMolecular ConformationSerotoninSerotonin Plasma Membrane Transport ProteinsSelective Serotonin Reuptake InhibitorsSmall Molecule Libraries

Comments(0)

Metadata

Study TypeObservational

SourcePubMed

Publication DateMay 16, 2023

Citations0

External Links

PView on PubMed DView DOI

Cite this study

X LinkedIn Email