Structure-based discovery of conformationally selective inhibitors of the serotonin transporter
| Autor: | Isha Singh, Anubha Seth, Christian B. Billesbølle, Joao Braz, Ramona M. Rodriguiz, Kasturi Roy, Bethlehem Bekele, Veronica Craik, Xi-Ping Huang, Danila Boytsov, Vladimir M. Pogorelov, Parnian Lak, Henry O’Donnell, Walter Sandtner, John J. Irwin, Bryan L. Roth, Allan I. Basbaum, William C. Wetsel, Aashish Manglik, Brian K. Shoichet, Gary Rudnick |
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| Rok vydání: | 2023 |
| Předmět: |
Serotonin Plasma Membrane Transport Proteins
Serotonin serotonin transporter Molecular Conformation Neurosciences Biological Sciences ultra-large libraries Medical and Health Sciences General Biochemistry Genetics and Molecular Biology Small Molecule Libraries Mice Substance Misuse Fluoxetine Ibogaine depression docking Animals functional selectivity Drug Abuse (NIDA only) Selective Serotonin Reuptake Inhibitors Developmental Biology |
| Zdroj: | Cell, vol 186, iss 10 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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