对带有噻唑烷二酮弹头的配体与人类组蛋白去乙酰化酶4结合的机制性见解。
Mechanistic Insights into Binding of Ligands with Thiazolidinedione Warhead to Human Histone Deacetylase 4.
作者信息
Schweipert Markus, Jänsch Niklas, Upadhyay Neha, Tilekar Kalpana, Wozny Ewelina, Basheer Sidra, Wurster Eva, Müller Marlene, C S Ramaa, Meyer-Almes Franz-Josef
机构信息
Department of Chemical Engineering and Biotechnology, University of Applied Sciences, 64295 Darmstadt, Germany.
Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai 400614, India.
出版信息
Pharmaceuticals (Basel). 2021 Oct 11;14(10):1032. doi: 10.3390/ph14101032.
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.
最近，我们报道了非异羟肟酸噻唑烷二酮（TZD）类似物能够抑制人去乙酰化酶4（HDAC4）。本研究旨在剖析HDAC4对TZD配体进行分子识别的分子决定因素和动力学。为此，对225种类似物进行了构效关系分析，并结合对多种HDAC4突变体变体的酶学和结合动力学的全面研究。通过与HDAC4的两种主要构象对接，对实验数据进行了合理化分析。TZD配体是竞争性抑制剂，通过涉及主要分子识别和诱导契合的两步机制结合。24 g的停留时间为（34±3）分钟，因此比经典的泛HDAC抑制剂SAHA的停留时间（（5±2）分钟）长得多。重要的是，结合动力学可以通过改变CAP基团的结构来调节。
Zotero 插件