Docking large libraries of molecules against unrefined AlphaFold2 (AF2) models of the σ2 and serotonin 2A (5-HT2A) receptors produced hit rates and affinities as high as those obtained by docking against experimental structures. These results were achieved despite differences in orthosteric residue conformations between the AF2 models and the experimental structures. A cryo–electron microscopy structure of one potent 5-HT2A ligand identified from AF2 docking showed residue accommodations similar to the AF2 prediction. AF2 models may sample low-energy conformations that differ from experimental structures but remain useful for ligand discovery, extending the reach of structure-based drug design.
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.