Journal: Cell / Year: 2023 Title: Structure-based discovery of conformationally selective inhibitors of the serotonin transporter. Authors: 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 ...Authors: 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 / 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 ...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.
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