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.

血清素转运蛋白(SERT) 消除突触血清素，是抗抑郁药物的目标。SERT采用三种构象：外开、闭塞、内开。所有已知的抑制剂都以外开状态为目标，但伊博加因除外，伊博加因具有不寻常的抗抑郁和物质戒断作用，并稳定内开构象。不幸的是，伊博加因的混杂性和心脏毒性限制了对内向开放态配体的理解。我们将超过 2 亿个小分子与 SERT 的向内开放状态对接。合成了 36 种顶级化合物，其中 13 种被抑制；进一步基于结构的优化导致选择了两种有效的（低纳摩尔）抑制剂。这些稳定了 SERT 的外向封闭状态，几乎没有针对常见脱靶的活动。其中一个与 SERT 结合的冷冻电镜结构证实了预测的几何形状。在小鼠行为测定中，这两种化合物都具有抗焦虑和抗抑郁样活性，其效力比其他化合物强 200 倍。氟西汀（百忧解），以及一种可显着逆转吗啡戒断效应的药物。