Though AlphaFold2 (AF2) models have had wide impact, they have had mixed success in retrospective ligand recognition. Here, we prospectively docked large libraries against unrefined AF2 models of the σ2 and 5-HT2A receptors, testing hundreds of new molecules and comparing results to docking against the experimental structures. Hit rates were high and similar for the experimental and the AF2 structures, as were affinities. The success of docking against the AF2 models was achieved despite differences in orthosteric residue conformations versus the experimental structures. Determination of the cryoEM structure for one of the more potent 5HT2A ligands from the AF2 docking revealed residue accommodations that resembled the AF2 prediction. AF2 models may sample conformations that differ from experimental structures but remain low energy and relevant for ligand discovery, extending the domain of structure-based ligand discovery. This repository contains docked poses shown in this study.

The data contain:

1) AlphaFold2 models of the σ2 and 5HT2A receptors used to generate these two docked poses:

• AF-Q5BJF2-F1-model_v1_prep.pdb is the AlphaFold2 model used for docking against the σ2 receptor.
• AF-P28223-F1-model_v1_prep.pdb is the AlphaFold2 model used for docking against the 5HT2A receptor.

2) Docked poses of ZINC866533340 in the σ2 model and Z7757 (ZINClB000002x4yW) in the 5HT2A model:

• ZINC000866533340_af.mol2 is the docked pose of ZINC866533340 in the σ2 model.
• 7757_af.mol2 is the docked pose of Z7757 (ZINClB000002x4yW) in the 5HT2A model.