Computer- and NMR-aided design of small-molecule inhibitors of the Hub1 protein
| Autor: | Atilio Reyes Romero, Katarzyna Kubica, Radoslaw Kitel, Ismael Rodríguez, Katarzyna Magiera-Mularz, Alexander Dömling, Tad A. Holak, Ewa Surmiak |
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| Přispěvatelé: | Drug Design, Medicinal Chemistry and Bioanalysis (MCB) |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Magnetic Resonance Spectroscopy
Binding Sites protein-peptide docking Computers Organic Chemistry protein-protein interactions Pharmaceutical Science Ligands Analytical Chemistry small-molecule inhibitors Alternative Splicing nuclear magnetic resonance Chemistry (miscellaneous) Drug Discovery Spliceosomes Molecular Medicine Humans anti-cancer therapy Physical and Theoretical Chemistry Ubiquitins Protein Binding |
| Zdroj: | Molecules, 27(23):8282. MDPI AG Molecules; Volume 27; Issue 23; Pages: 8282 |
| ISSN: | 1431-5157 |
| Popis: | By binding to the spliceosomal protein Snu66, the human ubiquitin-like protein Hub1 is a modulator of the spliceosome performance and facilitates alternative splicing. Small molecules that bind to Hub1 would be of interest to study the protein-protein interaction of Hub1/Snu66, which is linked to several human pathologies, such as hypercholesterolemia, premature aging, neurodegenerative diseases, and cancer. To identify small molecule ligands for Hub1, we used the interface analysis, peptide modeling of the Hub1/Snu66 interaction and the fragment-based NMR screening. Fragment-based NMR screening has not proven sufficient to unambiguously search for fragments that bind to the Hub1 protein. This was because the Snu66 binding pocket of Hub1 is occupied by pH-sensitive residues, making it difficult to distinguish between pH-induced NMR shifts and actual binding events. The NMR analyses were therefore verified experimentally by microscale thermophoresis and by NMR pH titration experiments. Our study found two small peptides that showed binding to Hub1. These peptides are the first small-molecule ligands reported to interact with the Hub1 protein. |
| Databáze: | OpenAIRE |
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