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- W4377029605 abstract "<b>Abstract ID 52403</b> <b>Poster Board 123</b> Ligand-binding promiscuity in detoxification systems protects the body from toxicological harm but is a roadblock to drug development due to the difficulty in optimizing small molecules to both retain target potency and avoid metabolic events. Immense effort is invested in evaluating metabolism of molecules to develop safer, more effective treatments, but engineering specificity into or out of promiscuous proteins and their ligands is a challenging task. To better understand the promiscuous nature of detoxification networks, we have used X-ray crystallography to characterize a structural feature of pregnane X receptor (PXR), a nuclear receptor that is activated by diverse molecules (with different structures and sizes) to upregulate transcription of drug metabolism genes. We found that large ligands expand PXR’s ligand binding pocket, and the ligand-induced expansion occurs through a specific unfavorable compound-protein clash that likely contributes to reduced binding affinity. Removing the clash by compound modification resulted in more favorable binding modes with significantly enhanced binding affinity. We then engineered the unfavorable ligand-protein clash into a potent, small PXR ligand, resulting in marked reduction of PXR binding and activation. Structural analysis showed that PXR is remodeled and that the modified ligands reposition in the binding pocket to avoid clashes, but the combined protein/ligand conformational changes result in less favorable binding modes. Thus, ligand-induced binding pocket expansion increases ligand-binding potential of PXR but is an unfavorable event; therefore, drug candidates can be engineered to expand PXR9s ligand binding pocket and reduce their safety liability due to PXR binding. Research reported in this publication was supported by ALSAC and National Institutes of Health National Institute of General Medical Sciences [Grant R35GM118041]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work utilized the FMX and AMX beamlines, which are primarily supported by the National Institutes of Health National Institute of General Medical Sciences through a Center Core P30 Grant (P30GM133893), and by the U.S. Department of Energy Office of Biological and Environmental Research (KP1607011). As part of the National Synchrotron Light Source II, a national user facility at Brookhaven National Laboratory, work performed at the Center for BioMolecular Structures is supported in part by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences Program under contract number DE-SC0012704." @default.
- W4377029605 created "2023-05-19" @default.
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- W4377029605 date "2023-05-18" @default.
- W4377029605 modified "2023-09-29" @default.
- W4377029605 title "Structure-guided approach to modulate small molecule binding to the promiscuous pregnane X receptor" @default.
- W4377029605 doi "https://doi.org/10.1124/jpet.122.524030" @default.
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