Highlights •Large-library docking finds conformationally and target-selective SERT inhibitors •Cryo-EM supports the computationally predicted structure •The inhibitors are anti-depressant-like and alleviate opioid withdrawal in mice •Targeting of transporters for structure-based ligand discovery   5-hydroxytryptamine transporter (SERT) is a common target for antidepressants as it can “transport” serotonin from synapses.   Transporting protein transporters is a process of “swallowing and vomiting”, completed by alternating protein conformations opening outward and inward. Research…