Structure-based discovery of conformationally selective inhibitors of the serotonin transporter.
- 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;
- Rudnick, Gary
- et al.
Published Web Location
https://www.cell.com/cell/pdf/S0092-8674(23)00406-3.pdfhttps://www.cell.com/cell/pdf/S0092-8674(23)00406-3.pdfAbstract
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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