Mapping Ligand Interactions of Bromodomains BRD4 and ATAD2 with FragLites and PepLites─Halogenated Probes of Druglike and Peptide-like Molecular Interactions
| العنوان: | Mapping Ligand Interactions of Bromodomains BRD4 and ATAD2 with FragLites and PepLites─Halogenated Probes of Druglike and Peptide-like Molecular Interactions |
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| المؤلفون: | Gemma Davison, Mathew P. Martin, Shannon Turberville, Selma Dormen, Richard Heath, Amy B. Heptinstall, Marie Lawson, Duncan C. Miller, Yi Min Ng, James N. Sanderson, Ian Hope, Daniel J. Wood, Céline Cano, Jane A. Endicott, Ian R. Hardcastle, Martin E. M. Noble, Michael J. Waring |
| المصدر: | Journal of Medicinal Chemistry. 65:15416-15432 |
| بيانات النشر: | American Chemical Society (ACS), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Binding Sites, Protein Domains, Drug Discovery, Nuclear Proteins, Molecular Medicine, Cell Cycle Proteins, Ligands, Crystallography, X-Ray, Peptides, Transcription Factors, Protein Binding |
| الوصف: | The development of ligands for biological targets is critically dependent on the identification of sites on proteins that bind molecules with high affinity. A set of compounds, called FragLites, can identify such sites, along with the interactions required to gain affinity, by X-ray crystallography. We demonstrate the utility of FragLites in mapping the binding sites of bromodomain proteins BRD4 and ATAD2 and demonstrate that FragLite mapping is comparable to a full fragment screen in identifying ligand binding sites and key interactions. We extend the FragLite set with analogous compounds derived from amino acids (termed PepLites) that mimic the interactions of peptides. The output of the FragLite maps is shown to enable the development of ligands with leadlike potency. This work establishes the use of FragLite and PepLite screening at an early stage in ligand discovery allowing the rapid assessment of tractability of protein targets and informing downstream hit-finding. |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.2c01357 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a4f5f45f4a2b13dc353a06e52583b772 https://doi.org/10.1021/acs.jmedchem.2c01357 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a4f5f45f4a2b13dc353a06e52583b772 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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| DOI: | 10.1021/acs.jmedchem.2c01357 |