锌螯合作用与组蛋白去乙酰化酶中的偕氨肟作用受连接通道中水进入的调节。
Zinc chelation with hydroxamate in histone deacetylases modulated by water access to the linker binding channel.
机构信息
Department of Chemistry and State Key Laboratory of Physical Chemistry of Solid Surfaces, Xiamen University, Xiamen 361005, China.
出版信息
J Am Chem Soc. 2011 Apr 27;133(16):6110-3. doi: 10.1021/ja111104p. Epub 2011 Apr 1.
Abstract
It is of significant biological interest and medical importance to develop class- and isoform-selective histone deacetylase (HDAC) modulators. The impact of the linker component on HDAC inhibition specificity has been revealed but is not understood. Using Born-Oppenheimer ab initio QM/MM MD simulations, a state-of-the-art approach to simulating metallo-enzymes, we have found that the hydroxamic acid remains to be protonated upon its binding to HDAC8, and thus disproved the mechanistic hypothesis that the distinct zinc-hydroxamate chelation modes between two HDAC subclasses come from different protonation states of the hydroxamic acid. Instead, our simulations suggest a novel mechanism in which the chelation mode of hydroxamate with the zinc ion in HDACs is modulated by water access to the linker binding channel. This new insight into the interplay between the linker binding and the zinc chelation emphasizes its importance and gives guidance regarding linker design for the development of new class-IIa-specific HDAC inhibitors.
摘要
开发具有类别和同工型选择性的组蛋白去乙酰化酶（HDAC）调节剂具有重要的生物学意义和医学重要性。连接子组件对 HDAC 抑制特异性的影响已经被揭示出来，但尚未被理解。使用 Born-Oppenheimer 从头算 QM/MM MD 模拟，这是一种模拟金属酶的最先进方法，我们发现，当羟肟酸与 HDAC8 结合时，其仍然保持质子化状态，从而否定了这样一种机制假说，即两个 HDAC 亚类之间不同的锌-羟肟酸螯合模式来自于羟肟酸的不同质子化状态。相反，我们的模拟表明了一种新的机制，其中羟肟酸与 HDAC 中锌离子的螯合模式通过连接子结合通道中水的进入来调节。这种对连接子结合与锌螯合之间相互作用的新见解强调了其重要性，并为新型 IIa 类特异性 HDAC 抑制剂的开发提供了连接子设计方面的指导。
相似文献
1
Zinc chelation with hydroxamate in histone deacetylases modulated by water access to the linker binding channel.锌螯合作用与组蛋白去乙酰化酶中的偕氨肟作用受连接通道中水进入的调节。
J Am Chem Soc. 2011 Apr 27;133(16):6110-3. doi: 10.1021/ja111104p. Epub 2011 Apr 1.
2
Thiol versus hydroxamate as zinc binding group in HDAC inhibition: An ab initio QM/MM molecular dynamics study.硫醇与异羟肟酸作为组蛋白去乙酰化酶（HDAC）抑制中锌结合基团的比较：从头算量子力学/分子力学分子动力学研究
J Comput Chem. 2015 Nov 15;36(30):2228-35. doi: 10.1002/jcc.24203. Epub 2015 Oct 9.
3
Computational exploration of zinc binding groups for HDAC inhibition.计算探索组锌结合的 HDAC 抑制。
J Org Chem. 2013 May 17;78(10):5051-5. doi: 10.1021/jo400406g. Epub 2013 Apr 29.
4
Structure-function analysis of the conserved tyrosine and diverse π-stacking among class I histone deacetylases: a QM (DFT)/MM MD study.基于 QM（DFT）/MM MD 的 I 类组蛋白去乙酰化酶保守酪氨酸和多样π-堆积的结构-功能分析。
J Chem Inf Model. 2014 Nov 24;54(11):3162-71. doi: 10.1021/ci500513n. Epub 2014 Nov 6.
5
A structure-based virtual screening approach toward the discovery of histone deacetylase inhibitors: identification of promising zinc-chelating groups.基于结构的虚拟筛选方法发现组蛋白去乙酰化酶抑制剂：有希望的锌螯合基团的鉴定。
ChemMedChem. 2010 Apr 6;5(4):591-7. doi: 10.1002/cmdc.200900500.
6
Diarylcyclopropane hydroxamic acid inhibitors of histone deacetylase 4 designed by combinatorial approach and QM/MM calculations.组合方法和 QM/MM 计算设计的组蛋白去乙酰化酶 4 的二芳基环丙烷羟肟酸抑制剂。
J Mol Graph Model. 2018 Oct;85:97-110. doi: 10.1016/j.jmgm.2018.08.008. Epub 2018 Aug 16.
7
Quantum polarized ligand docking investigation to understand the significance of protonation states in histone deacetylase inhibitors.量子极化配体对接研究，以了解组蛋白去乙酰化酶抑制剂中质子化状态的意义。
J Mol Graph Model. 2013 Jul;44:44-53. doi: 10.1016/j.jmgm.2013.05.002. Epub 2013 May 14.
8
A cyclodextrin-capped histone deacetylase inhibitor.一种环糊精封端的组蛋白去乙酰化酶抑制剂。
Bioorg Med Chem Lett. 2013 Jun 1;23(11):3346-8. doi: 10.1016/j.bmcl.2013.03.084. Epub 2013 Apr 2.
9
Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor.一种真核生物锌依赖性组蛋白脱乙酰酶——人类HDAC8与一种异羟肟酸抑制剂复合物的晶体结构。
Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15064-9. doi: 10.1073/pnas.0404603101. Epub 2004 Oct 11.
10
Zinc binding in HDAC inhibitors: a DFT study.组蛋白去乙酰化酶抑制剂中的锌结合：一项密度泛函理论研究。
J Org Chem. 2007 Jul 6;72(14):5446-9. doi: 10.1021/jo070739s. Epub 2007 Jun 19.
引用本文的文献
1
Enhancing HDAC Inhibitor Screening: Addressing Zinc Parameterization and Ligand Protonation in Docking Studies.增强组蛋白去乙酰化酶抑制剂筛选：解决对接研究中的锌参数化和配体质子化问题。
Int J Mol Sci. 2025 Jan 20;26(2):850. doi: 10.3390/ijms26020850.
2
The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods.组蛋白去乙酰化酶家族：结构特征及联合计算方法的应用
Pharmaceuticals (Basel). 2024 May 10;17(5):620. doi: 10.3390/ph17050620.
3
A Review on Molecular Docking on HDAC Isoforms: Novel Tool for Designing Selective Inhibitors.组蛋白去乙酰化酶亚型的分子对接研究综述：设计选择性抑制剂的新工具
Pharmaceuticals (Basel). 2023 Nov 22;16(12):1639. doi: 10.3390/ph16121639.
4
Harnessing the Role of HDAC6 in Idiopathic Pulmonary Fibrosis: Design, Synthesis, Structural Analysis, and Biological Evaluation of Potent Inhibitors.利用组蛋白去乙酰化酶 6 在特发性肺纤维化中的作用：有效抑制剂的设计、合成、结构分析和生物学评价。
J Med Chem. 2021 Jul 22;64(14):9960-9988. doi: 10.1021/acs.jmedchem.1c00184. Epub 2021 Jul 12.
5
Histone deacetylase 10, a potential epigenetic target for therapy.组蛋白去乙酰化酶 10，一种有治疗潜力的表观遗传学靶点。
Biosci Rep. 2021 Jun 25;41(6). doi: 10.1042/BSR20210462.
6
Fragment-Based Drug Design of Selective HDAC6 Inhibitors.选择性组蛋白去乙酰化酶6（HDAC6）抑制剂的基于片段的药物设计
Methods Mol Biol. 2021;2266:155-170. doi: 10.1007/978-1-0716-1209-5_9.
7
Novel 4-Oxoquinazoline-Based -Hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Biological Evaluation.基于新型4-氧代喹唑啉的β-羟基丙烯酰胺类组蛋白去乙酰化酶抑制剂：设计、合成及生物学评价
ACS Omega. 2021 Feb 8;6(7):4907-4920. doi: 10.1021/acsomega.0c05870. eCollection 2021 Feb 23.
8
Catalytic Roles of Coenzyme Pyridoxal-5'-phosphate (PLP) in PLP-dependent Enzymes: Reaction Pathway for Methionine-γ-lyase-catalyzed L-methionine Depletion.辅酶磷酸吡哆醛（PLP）在依赖PLP的酶中的催化作用：甲硫氨酸γ-裂合酶催化L-甲硫氨酸消耗的反应途径。
ACS Catal. 2020 Feb 7;10(3):2198-2210. doi: 10.1021/acscatal.9b03907. Epub 2020 Jan 13.
9
Molecular Docking Simulations on Histone Deacetylases (HDAC)-1 and -2 to Investigate the Flavone Binding.针对组蛋白去乙酰化酶（HDAC）-1和-2的分子对接模拟以研究黄酮类化合物的结合情况。
Biomedicines. 2020 Dec 4;8(12):568. doi: 10.3390/biomedicines8120568.
10
A short guide to histone deacetylases including recent progress on class II enzymes.组蛋白去乙酰化酶简介，包括 II 类酶的最新进展。
Exp Mol Med. 2020 Feb;52(2):204-212. doi: 10.1038/s12276-020-0382-4. Epub 2020 Feb 19.
本文引用的文献
1
Tinker 8: Software Tools for Molecular Design.Tinker 8：分子设计软件工具。
J Chem Theory Comput. 2018 Oct 9;14(10):5273-5289. doi: 10.1021/acs.jctc.8b00529. Epub 2018 Sep 19.
2
A proton-shuttle reaction mechanism for histone deacetylase 8 and the catalytic role of metal ions.组蛋白去乙酰化酶 8 的质子穿梭反应机制及金属离子的催化作用。
J Am Chem Soc. 2010 Jul 14;132(27):9471-9. doi: 10.1021/ja103932d.
3
Catalytic reaction mechanism of acetylcholinesterase determined by Born-Oppenheimer ab initio QM/MM molecular dynamics simulations.通过 Born-Oppenheimer 从头算 QM/MM 分子动力学模拟确定乙酰胆碱酯酶的催化反应机制。
J Phys Chem B. 2010 Jul 8;114(26):8817-25. doi: 10.1021/jp104258d.
4
Inside HDAC with HDAC inhibitors.与 HDAC 抑制剂一起进入 HDAC。
Eur J Med Chem. 2010 Jun;45(6):2095-116. doi: 10.1016/j.ejmech.2010.02.030. Epub 2010 Feb 14.
5
Flexibility of Catalytic Zinc Coordination in Thermolysin and HDAC8: A Born-Oppenheimer ab initio QM/MM Molecular Dynamics Study.嗜热菌蛋白酶和组蛋白去乙酰化酶8中催化锌配位的灵活性：玻恩-奥本海默从头算量子力学/分子力学分子动力学研究
J Chem Theory Comput. 2009 Dec 2;6(1):337. doi: 10.1021/ct9005322.
6
Chemical phylogenetics of histone deacetylases.组蛋白去乙酰化酶的化学系统发育学
Nat Chem Biol. 2010 Mar;6(3):238-243. doi: 10.1038/nchembio.313. Epub 2010 Feb 7.
7
Discovery of potent and selective histone deacetylase inhibitors via focused combinatorial libraries of cyclic alpha3beta-tetrapeptides.通过环α3β-四肽聚焦组合文库发现强效和选择性组蛋白脱乙酰酶抑制剂。
J Med Chem. 2009 Dec 10;52(23):7836-46. doi: 10.1021/jm900850t.
8
Active site cysteine is protonated in the PAD4 Michaelis complex: evidence from Born-Oppenheimer ab initio QM/MM molecular dynamics simulations.在PAD4米氏复合物中活性位点半胱氨酸被质子化：来自玻恩-奥本海默从头算量子力学/分子力学分子动力学模拟的证据。
J Phys Chem B. 2009 Sep 24;113(38):12750-8. doi: 10.1021/jp903173c.
9
The many roles of histone deacetylases in development and physiology: implications for disease and therapy.组蛋白去乙酰化酶在发育和生理学中的多种作用：对疾病和治疗的影响。
Nat Rev Genet. 2009 Jan;10(1):32-42. doi: 10.1038/nrg2485.
10
Structural studies of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors.人类组蛋白去乙酰化酶8及其与底物和抑制剂复合的位点特异性变体的结构研究。
Biochemistry. 2008 Dec 23;47(51):13554-63. doi: 10.1021/bi801610c.
Zotero 插件