Cited by 114Histone Deacetylase Inhibitors ResearchEnzyme function and inhibitionChemical Reaction Mechanisms

Zinc Chelation with Hydroxamate in Histone Deacetylases Modulated by Water Access to the Linker Binding Channel

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Wu, Ruibo, Lu, Zhenyu, Cao, Zexing, Zhang, Yingkai·2011·Journal of the American Chemical Society

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.

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Crossref · 10.1021/ja111104p

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  • Spherical potentials are especially suitable for accurately reproducing hydroxamate coordination geometries.

    “Spherical potentials are particularly suitable for accurately reproducing hydroxamate coordination geometries.39,40”

    From AutoDock4<sub>Zn</sub>: An Improved AutoDock Force Field for Small-Molecule Docking to Zinc Metalloproteins (2014) · cites this paper as [39]

    The paper’s discussion of QM/MM simulations says they reproduced hydroxamate coordination configurations in HDAC8 and HDAC7, but it does not identify spherical potentials as the method responsible. Searches for spherical potentials and their suitability for reproducing coordination geometry found no passage addressing that claim (page unavailable in our copy). (LLM, conf=0.73)

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Research works printed but not linked: 1

  1. [35]Corminboeuf C Hu P Tuckerman ME Zhang YK J. Am. Chem. Soc 2006 128 4530 4531 16594663

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Authors
Wu, R., Lu, Z., Cao, Z., & Zhang, Y.
Affiliations
  • Xiamen University (CN)
  • New York University (US)
Corresponding author
  • Cao, Zexing
  • Zhang, Yingkai
Venue
Journal of the American Chemical Society
Published
2011-04-01
Volume
133
Issue
16
Pages
6110-6113
ISSN
  • 0002-7863 (ISSN-L)
  • 1520-5126
OpenAlex
W1988811573
Cited by
108
References
39
Citations by year
2026: 3 · 2025: 6 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 6 · 2020: 8 · 2019: 9 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 9 · 2014: 15 · 2013: 8 · 2012: 7
FWCI
4.15
Type
journal article
Language
en
Open access
Locations
  • Journal of the American Chemical Society (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of General Medical Sciences (R01GM079223)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
Keywords
histone deacetylase, HDAC8, zinc chelation, hydroxamate, water access, isoform-selective inhibitors
MeSH terms
Chelating Agents, Histone Deacetylases, Hydrogen Bonding, Hydroxamic Acids, Quantum Theory, Water, Zinc

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