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