Structure-based discovery of conformationally selective inhibitors of the serotonin transporter.
Isha Singh, Anubha Seth, Christian B. Billesbølle, Joao M 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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Computational docking and experimental validation Peer reviewed |
|---|---|
| Population | Mice |
| Topics | Addiction Depression Serotonin |
| Keywords | Docking Functional selectivity Serotonin transporter Potent compounds Promising path Screened molecules Pharmacology anti-depressant effects Anti-anxiety effects Reversing morphine withdrawal Improved safety Neuroscience anti-depressant Screened ultra-large libraries |
| Citations | 97 |
| Key findings | 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.