Thermodynamics of ligand binding to histone deacetylase like amidohydrolase from Bordetella/Alcaligenes

Meyners, Christian; Baud, Matthias G. J.; Fuchter, Matthew J.; Meyer‐Almes, Franz‐Josef

doi:10.1002/jmr.2345

Cited by 7 publications

(21 citation statements)

References 39 publications

(46 reference statements)

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“…Dansyl probes containing hydroxamic acid were synthesized according to Meyners, Baud, Fuchter, & Meyer‐Almes, a and Dioxolobenzodioxol (DBD)‐probes according to Refs. (Meyners, Baud, Fuchter, & Meyer‐Almes, ) and (Meyners, Mertens, Wessig, & Meyer‐Almes, ). HDAH pa was prepared as described elsewhere (Meyners, Baud, Fuchter, & Meyer‐Almes, ).…”

Section: Methodsmentioning

confidence: 99%

Determination of the binding mechanism of histone deacetylase inhibitors

Meyer‐Almes

2018

Chem Biol Drug Des

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This article places its focus on methods and tools enabling the elucidation of the mechanism by which ligands, small‐molecule inhibitors, or substrates interact with zinc‐containing bacterial or human members of the histone deacetylase family (HDACs). These methods include biochemical and biophysical approaches and can be subdivided into equilibrium and kinetic methods. More information about the exact mode of action can be obtained by combining these methods with specific mutant variants of the enzymes and/or series of structural similar ligands. All available equilibrium and kinetic data including additional information from 3D structures of HDAC–ligand complexes can be beneficially combined in a data analysis procedure called Integrated Global‐Fit analysis eventually providing the most likely binding mechanism.

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Section: Methodsmentioning

confidence: 99%

Determination of the binding mechanism of histone deacetylase inhibitors

Meyer‐Almes

2018

Chem Biol Drug Des

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“…[19] HDAH pa was prepared as described elsewhere. SAHA was obtained from Cayman Chemical (USA), and PFSAHA was bought from Synchem OHG (Germany).…”

Section: Methodsmentioning

confidence: 99%

“…[19] For the determination of the equilibrium dissociation constant, K d of the fluorescent dansyl conjugates 1a-f varying concentrations of the respective dansyl conjugate were incubated with 0.2 μM HDAH pa in microplates for 30 min at 30°C. [19] For the determination of the equilibrium dissociation constant, K d of the fluorescent dansyl conjugates 1a-f varying concentrations of the respective dansyl conjugate were incubated with 0.2 μM HDAH pa in microplates for 30 min at 30°C.…”

Section: Fret Binding Assaymentioning

confidence: 99%

“…[2,19] Although the two compounds with the highest enthalpic portion are among the most selective ones, a higher enthalpic portion correlates only for HDACs 3, 4, 5, and 8 significantly (p-value < .05) with increased selectivity (Figure 4 and Fig. Association kinetic traces of varying concentrations of 1d to HDAH pa (A-F) as well as the equilibrium binding curve (g) were fitted simultaneously to the indicated binding model (h).…”

Section: Thermodynamic Parameters To Assess the Selectivity Of Hdahmentioning

confidence: 99%

“…[15][16][17][18][19] HDAHs have been used before as model systems for the histone deacetylase family including the closely related pharmacologically most relevant human histone deacetylases (HDACs) and show highest similarity to human HDAC6.…”

Section: Introductionmentioning

confidence: 99%

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Impact of binding mechanism on selective inhibition of histone deacetylase isoforms

Meyners

Meyer‐Almes

2017

Chem Biol Drug Des

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Industrialized drug screening campaigns usually deliver hundreds of compounds that are active on a particular pharmaceutical target. In light of high failure rates of drug candidates due to unforeseeable off-target toxicity, the early identification of the most promising compounds with high potential for target selectivity is an urgent need to improve the quality of lead compounds and lower attrition rates in the drug development process. The reliable prediction of the selectivity of active substances for a target protein is a challenging task. A comprehensive study of the binding kinetics, thermodynamics, and selectivity of chemically related ligands of histone deacetylase (HDAC) like amidohydrolase from Pseudomonas aeruginosa (HDAH ) reveals one general binding mechanism for all analyzed compounds consisting of a preceding conformational selection step followed by an optional subsequent induced fit. Depending on the chemical structure, the ligands bind to one or two of at least three protein conformations with different rate constants. Although these kinetic and mechanistic differences hamper the predictability of selectivity for the HDAC inhibitors, we demonstrate that the enthalpy-weighted binding constant KdΔH is a useful metric to predict isoform selectivity of inhibitors against HDAC enzymes and relatively robust toward different but related binding mechanisms.

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A Fluorescence‐Lifetime‐Based Binding Assay for Class IIa Histone Deacetylases

Meyners

Mertens

Wessig

et al. 2017

Chemistry A European J

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Class IIa histone deacetylases (HDACs) show extremely low enzymatic activity and no commonly accepted endogenous substrate is known today. Increasing evidence suggests that these enzymes exert their effect rather through molecular recognition of acetylated proteins and recruiting other proteins like HDAC3 to the desired target location. Accordingly, class IIa HDACs like bromodomains have been suggested to act as "Readers" of acetyl marks, whereas enzymatically active HDACs of class I or IIb are called "Erasers" to highlight their capability to remove acetyl groups from acetylated histones or other proteins. Small-molecule ligands of class IIa histone deacetylases (HDACs) have gained tremendous attention during the last decade and have been suggested as pharmaceutical targets in several indication areas such as cancer, Huntington's disease and muscular atrophy. Up to now, only enzyme activity assays with artificial chemically activated trifluoroacetylated substrates are in use for the identification and characterization of new active compounds against class IIa HDACs. Here, we describe the first binding assay for this class of HDAC enzymes that involves a simple mix-and-measure procedure and an extraordinarily robust fluorescence lifetime readout based on [1,3]dioxolo[4,5-f]benzodioxole-based ligand probes. The principle of the assay is generic and can also be transferred to class I HDAC8.

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Thermodynamics of ligand binding to histone deacetylase like amidohydrolase from Bordetella/Alcaligenes

Cited by 7 publications

References 39 publications

Determination of the binding mechanism of histone deacetylase inhibitors

Determination of the binding mechanism of histone deacetylase inhibitors

Impact of binding mechanism on selective inhibition of histone deacetylase isoforms

A Fluorescence‐Lifetime‐Based Binding Assay for Class IIa Histone Deacetylases

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