학술논문
Structure-based discovery of conformationally selective inhibitors of the serotonin transporter.
Document Type
article
Author
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
Source
Cell. 186(10)
Subject
Language
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.