Automatic and accurate ligand structure determination guided by cryo-electron microscopy maps

Muenks, Andrew; Zepeda, Samantha K; Zhou, Guangfeng; Veesler, David; DiMaio, Frank

doi:10.1101/2022.08.16.504149

Cited by 1 publication

(2 citation statements)

References 51 publications

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“…The binding pose was further validated utilizing Emerald ( Extended Data Fig. 14 ), which uses a genetic algorithm to fit the ligand using the cryoEM density map as restraints 63 . The Cα-RMSD of the receptor was close to the lisuride structure (0.78Å) and recapitulated the receptor-Gαq interactions in prior 5-HT2AR structures ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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AlphaFold2 structures template ligand discovery

Lyu,

Kapolka,

Gumpper

et al. 2023

Preprint

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AlphaFold2 (AF2) and RosettaFold have greatly expanded the number of structures available for structure-based ligand discovery, even though retrospective studies have cast doubt on their direct usefulness for that goal. Here, we tested unrefined AF2 modelsprospectively, comparing experimental hit-rates and affinities from large library docking against AF2 models vs the same screens targeting experimental structures of the same receptors. Inretrospectivedocking screens against the σ2and the 5-HT2A receptors, the AF2 structures struggled to recapitulate ligands that we had previously found docking against the receptors’ experimental structures, consistent with published results.Prospectivelarge library docking against the AF2 models, however, yielded similar hit rates for both receptors versus docking against experimentally-derived structures; hundreds of molecules were prioritized and tested against each model and each structure of each receptor. The success of the AF2 models was achieved despite differences in orthosteric pocket residue conformations for both targets versus the experimental structures. Intriguingly, against the 5-HT2A receptor the most potent, subtype-selective agonists were discovered via docking against the AF2 model, not the experimental structure. To understand this from a molecular perspective, a cryoEM structure was determined for one of the more potent and selective ligands to emerge from docking against the AF2 model of the 5-HT2A receptor. Our findings suggest that AF2 models may sample conformations that are relevant for ligand discovery, much extending the domain of applicability of structure-based ligand discovery.

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Section: Resultsmentioning

confidence: 99%

“…Subsequent real-space refinement was carried out in phenix 71 and iterative manual fitting and adjustments were carried out with COOT 72 . The binding pose was further validated by using Emerald for Z7757 and the Gemspot pipeline for Lisuride 63 55 . Final model statistics were validated by Molprobity 73 ( Extended Data Table 1 ).…”

Section: Methodsmentioning

confidence: 99%