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Updated: Jun 26, 2025

Achieving Efficient Fragment Screening at XChem Facility at Diamond Light Source
Published on: May 29, 2021
AlphaFold2 structures guide prospective ligand discovery
Jiankun Lyu1,2, Nicholas Kapolka3, Ryan Gumpper3
1Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.
Abstract:
AlphaFold2 (AF2) models have had wide impact but mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 models of the σ2 and serotonin 2A (5-HT2A) receptors, testing hundreds of new molecules and comparing results with those obtained from docking against the experimental structures. Hit rates were high and similar for the experimental and AF2 structures, as were affinities. Success in docking against the AF2 models was achieved despite differences between orthosteric residue conformations in the AF2 models and the experimental structures. Determination of the cryo-electron microscopy structure for one of the more potent 5-HT2A 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 drug design.
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