| Autor: |
Markus Schweipert, Niklas Jänsch, Neha Upadhyay, Kalpana Tilekar, Ewelina Wozny, Sidra Basheer, Eva Wurster, Marlene Müller, Ramaa C S, Franz-Josef Meyer-Almes |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Pharmaceuticals, Vol 14, Iss 10, p 1032 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
1424-8247 |
| DOI: |
10.3390/ph14101032 |
| Popis: |
Recently, we have reported that non-hydroxamate thiazolidinedione (TZD) analogs are capable of inhibiting human deacetylase 4 (HDAC4). This study aims at the dissection of the molecular determinants and kinetics of the molecular recognition of TZD ligands by HDAC4. For this purpose, a structure activity relationship analysis of 225 analogs was combined with a comprehensive study of the enzyme and binding kinetics of a variety of HDAC4 mutant variants. The experimental data were rationalized by docking to the two major conformations of HDAC4. TZD ligands are competitive inhibitors and bind via a two-step mechanism involving principal molecular recognition and induced fit. The residence time of 24 g is (34 ± 3) min and thus much larger than that of the canonical pan-HDAC inhibitor SAHA ((5 ± 2) min). Importantly, the binding kinetics can be tuned by varying the structure of the CAP group. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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