ArticleJournal of the American Chemical Society2011
Zinc chelation with hydroxamate in histone deacetylases modulated by water access to the linker binding channel.
Article in Journal of the American Chemical Society, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 103 citations in OpenAlex.
- Exploration of 2-Mercaptoquinazolin-4(3H)-one Based N-Hydroxyheptanamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Anticancer Bioevaluation.Pharmaceutical research · 2025Article
- Enhancing HDAC Inhibitor Screening: Addressing Zinc Parameterization and Ligand Protonation in Docking Studies.International journal of molecular sciences · 2025Article
- The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods.Pharmaceuticals (Basel, Switzerland) · 2024Review
- A Review on Molecular Docking on HDAC Isoforms: Novel Tool for Designing Selective Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Harnessing the Role of HDAC6 in Idiopathic Pulmonary Fibrosis: Design, Synthesis, Structural Analysis, and Biological Evaluation of Potent Inhibitors.Journal of medicinal chemistry · 2021Article
- Histone deacetylase 10, a potential epigenetic target for therapy.Bioscience reports · 2021Review
- Novel 4-Oxoquinazoline-BasedACS omega · 2021Article
- Fragment-Based Drug Design of Selective HDAC6 Inhibitors.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Molecular Docking Simulations on Histone Deacetylases (HDAC)-1 and -2 to Investigate the Flavone Binding.Biomedicines · 2020Article
- OleD Loki as a Catalyst for Hydroxamate Glycosylation.Chembiochem : a European journal of chemical biology · 2020Article
- Catalytic Roles of Coenzyme Pyridoxal-5'-phosphate (PLP) in PLP-dependent Enzymes: Reaction Pathway for Methionine-γ-lyase-catalyzed L-methionine Depletion.ACS catalysis · 2020Article
- A short guide to histone deacetylases including recent progress on class II enzymes.Experimental & molecular medicine · 2020Review
- Purification and enzymatic assay of class I histone deacetylase enzymes.Methods in enzymology · 2019Article
- How accurate is the description of ligand-protein interactions by a hybrid QM/MM approach?Journal of molecular modeling · 2017Article
- Computational insights for the hydride transfer and distinctive roles of key residues in cholesterol oxidase.Scientific reports · 2017Article
- Probing Origin of Binding Difference of inhibitors to MDM2 and MDMX by Polarizable Molecular Dynamics Simulation and QM/MM-GBSA Calculation.Scientific reports · 2015Article
- Thiol versus hydroxamate as zinc binding group in HDAC inhibition: An ab initio QM/MM molecular dynamics study.Journal of computational chemistry · 2015Article
- Computational design of a time-dependent histone deacetylase 2 selective inhibitor.ACS chemical biology · 2015Article
- Valproic acid as a potential inhibitor of Plasmodium falciparum histone deacetylase 1 (PfHDAC1): an in silico approach.International journal of molecular sciences · 2015Article
- Mechanistic insights into a classic wonder drug--aspirin.Journal of the American Chemical Society · 2015Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.