Zinc Binding in HDAC Inhibitors:  A DFT Study

Wang, Difei; Helquist, Paul; Wiest, Olaf

doi:10.1021/jo070739s

Cited by 62 publications

(104 citation statements)

References 17 publications

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“…In addition, in some of these studies, the role played by the basic neighboring residues was not considered. 36 An exhaustive survey of the PDB led us to collect 121 structures of metalloenzymes bound to various ligands and with most having a resolution lower than 2.5 Å. The ligands cover a number of zinc binding groups (e.g., oamidoaniline, terminal sulfonamides, hydroxamic acids, thiols), and even include ligands bearing two potential zinc binding groups such as captopril cocrystallized with the angiotensin converting enzyme (pdb code: 2x8z, Figure 5) or a sulfanyl butanoic acid derivative (3i1u).…”

Section: Journal Of Chemical Information and Modelingmentioning

confidence: 99%

Docking Ligands into Flexible and Solvated Macromolecules. 6. Development and Application to the Docking of HDACs and other Zinc Metalloenzymes Inhibitors

Pottel

Therrien

Gleason

et al. 2014

J. Chem. Inf. Model.

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Metalloenzymes are ubiquitous proteins which feature one or more metal ions either directly involved in the enzymatic activity and/or structural properties (i.e., zinc fingers). Several members of this class take advantage of the Lewis acidic properties of zinc ions to carry out their various catalytic transformations including isomerization or amide cleavage. These enzymes have been validated as drug targets for a number of diseases including cancer; however, despite their pharmaceutical relevance and the availability of crystal structures, structure-based drug design methods have been poorly and indirectly parametrized for these classes of enzymes. More specifically, the metal coordination component and proton transfers of the process of drugs binding to metalloenzymes have been inadequately modeled by current docking programs, if at all. In addition, several known issues, such as coordination geometry, atomic charge variability, and a potential proton transfer from small molecules to a neighboring basic residue, have often been ignored. We report herein the development of specific functions and parameters to account for zinc-drug coordination focusing on the above-listed phenomena and their impact on docking to zinc metalloenzymes. These atom-type-dependent but atomic charge-independent functions implemented into Fitted 3.1 enable the simulation of drug binding to metalloenzymes, considering an acid-base reaction with a neighboring residue when necessary with good accuracy.

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Section: Journal Of Chemical Information and Modelingmentioning

confidence: 99%

Docking Ligands into Flexible and Solvated Macromolecules. 6. Development and Application to the Docking of HDACs and other Zinc Metalloenzymes Inhibitors

Pottel

Therrien

Gleason

et al. 2014

J. Chem. Inf. Model.

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“…Such a pK a would guarantee that the hydroxamate is neutral in solution at physiological pH, facilitating cell membrane permeation. However, upon coordination of the zinc ion, the pK a of hydroxamic acids would be reduced by approximately three units, the acidic proton being transferred to the adjacent conserved histidine (H669 in HDAC7) [80]. Interestingly, computational studies [41,66,[81][82][83] indicate that the anionic hydroxamate chelates the zinc ion in a bidentate fashion with geometries close to the experimental ones.…”

Section: Structural Features Important For Binding and Selectivity Ofmentioning

confidence: 74%

Histone deacetylases: structural determinants of inhibitor selectivity

Micelli

Rastelli

2015

Drug Discovery Today

158

112

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“…As for the zinc-binding ability of thiol, the results of density functional theory calculations suggested that the zinc-binding affinity of thiol is lower than that of hydroxamic acid. 84,85) On the hypothesis that discovery of a ZBG having zinc-binding affinity lower than hydroxamic acid could lead to the identification of isoform-selective HDAC inhibitors, we chose thiol as ZBG for further explorative study on isoform-selective HDAC inhibitors.…”

Section: )mentioning

confidence: 99%

Explorative Study on Isoform-Selective Histone Deacetylase Inhibitors

Suzuki

2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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Histone deacetylases (HDACs) catalyze the deacetylation of the acetylated lysine residues of histones and non-histone proteins, and are involved in various fundamental life phenomena, such as gene expression and cell cycle progression. Thus far, eighteen HDAC family members (HDAC1-11 and SIRT1-7) have been identified, but the functions of the HDAC isoforms are not yet fully understood. In addition, some of the HDAC isoforms have been suggested to be associated with various disease states, including cancer and neurodegenerative disorders. Therefore, isoform-selective HDAC inhibitors are of great interest, not only as tools for probing the biological functions of the isoforms, but also as candidate therapeutic agents with few side effects. It was against this background that we initiated research programs to identify isoform-selective HDAC inhibitors. We designed HDAC inhibitors based on the three-dimensional structure of the enzyme and on the proposed catalytic mechanism of HDACs, and found several isoform-selective HDAC inhibitors. Furthermore, we elucidated the functions of HDAC6 by chemical genetic approaches using these inhibitors. The results of this research also suggested the feasibility of using isoform-selective HDAC inhibitors as therapeutic agents.

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Zinc Binding in HDAC Inhibitors: A DFT Study

Cited by 62 publications

References 17 publications

Docking Ligands into Flexible and Solvated Macromolecules. 6. Development and Application to the Docking of HDACs and other Zinc Metalloenzymes Inhibitors

Docking Ligands into Flexible and Solvated Macromolecules. 6. Development and Application to the Docking of HDACs and other Zinc Metalloenzymes Inhibitors

Histone deacetylases: structural determinants of inhibitor selectivity

Explorative Study on Isoform-Selective Histone Deacetylase Inhibitors

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