Download MendeleyCovalent Modifier Discovery Using Hydrogen/Deuterium Exchange-Mass Spectrometry.
Kojima, H., Yanagi, R., Higuchi, E., Yoshizawa, M., Shimodaira, T., Kumagai, M., Kyoya, T., Sekine, M., Egawa, D., Ohashi, N., Ishida, H., Yamamoto, K., Itoh, T.(2023) J Med Chem 66: 4827-4839
- PubMed: 36994595
- DOI: https://doi.org/10.1021/acs.jmedchem.2c01986
- Primary Citation of Related Structures:
8HHP, 8HHQ - PubMed Abstract:
Covalent ligands are generally filtered out of chemical libraries used for high-throughput screening, because electrophilic functional groups are considered to be pan-assay interference compounds (PAINS). Therefore, screening strategies that can distinguish true covalent ligands from PAINS are required. Hydrogen/deuterium-exchange mass spectrometry (HDX-MS) is a powerful tool for evaluating protein stability. Here, we report a covalent modifier screening approach using HDX-MS. In this study, HDX-MS was used to classify peroxisome proliferator-activated receptor γ (PPARγ) and vitamin D receptor ligands. HDX-MS could discriminate the strength of ligand-protein interactions. Our HDX-MS screening method identified LT175 and nTZDpa, which can bind concurrently to the PPARγ ligand-binding domain (PPARγ-LBD) with synergistic activation. Furthermore, iodoacetic acid was identified as a novel covalent modifier that stabilizes the PPARγ-LBD.
Organizational Affiliation:
Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
