Structure-based discovery of conformationally selective inhibitors of the serotonin transporter.
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
Cell May 11, 2023 DOI: 10.1016/j.cell.2023.04.010 via PubMed
Summary
Docking over 200 million small molecules against the inward-open state of the serotonin transporter (SERT) identified two potent, low-nanomolar inhibitors that stabilize an outward-closed conformation. These compounds showed little activity against common off-targets, and a cryo-EM structure confirmed the predicted binding geometry. In mouse behavioral assays, both compounds exhibited anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold greater than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects. The work suggests a promising path toward new treatments for depression, anxiety, and addiction with improved safety.
Study at a glance
| Characteristics | Computational docking and experimental validation Peer reviewed |
|---|---|
| Population | Mice |
| Topics | Addiction Depression |
| Keywords | Docking Functional selectivity Serotonin transporter Potent compounds |
| Citations | 97 |
| Key finding | Two potent, low-nanomolar SERT inhibitors that stabilize an outward-closed state showed anxiolytic- and anti-depressant-like activity up to 200-fold better than fluoxetine in mice, and one reversed morphine withdrawal effects. |
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.