Mechanistic Insights into Binding of Ligands with Thiazolidinedione Warhead to Human Histone Deacetylase 4

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 acti...

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Published in:Pharmaceuticals (Basel, Switzerland) Switzerland), 2021-10, Vol.14 (10), p.1032
Main Authors: Schweipert, Markus, Jänsch, Niklas, Upadhyay, Neha, Tilekar, Kalpana, Wozny, Ewelina, Basheer, Sidra, Wurster, Eva, Müller, Marlene, C S, Ramaa, Meyer-Almes, Franz-Josef
Format: Article
Language:English
Subjects:
Amino acids
binding mechanism
Chromatography
Cooling
Enzymes
Ethanol
Human Histone Deacetylase 4 (HDAC4)
Ligands
Molecular weight
mutational study
Potash
Potassium
Proteins
thiazolidinediones
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Summary: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.
ISSN:1424-8247
1424-8247
DOI:10.3390/ph14101032