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Rapid Determination of Kinetic Constants for Slow-Binding Inhibitors and Inactivators of Human Histone Deacetylase 8

  • The kinetics and mechanism of drug binding to its target are critical to pharmacological efficacy. A high throughput (HTS) screen often results in hundreds of hits, of which usually only simple IC50 values are determined during reconfirmation. However, kinetic parameters such as residence time for reversible inhibitors and the kinact/KI ratio, which is the critical measure for evaluating covalent inactivators, are early predictive measures to assess the chances of success of the hits in the clinic. Using the promising cancer target human histone deacetylase 8 as an example, we present a robust method that calculates concentration-dependent apparent rate constants for the inhibition or inactivation of HDAC8 from dose–response curves recorded after different pre-incubation times. With these data, hit compounds can be classified according to their mechanism of action, and the relevant kinetic parameters can be calculated in a highly parallel fashion. HDAC8 inhibitors with known modes of action were correctly assigned to their mechanism, and the binding mechanisms of some hits from an internal HDAC8 screening campaign were newly determined. The oxonitriles SVE04 and SVE27 were classified as fast reversible HDAC8 inhibitors with moderate time-constant IC50 values of 4.2 and 2.6 µM, respectively. The hit compound TJ-19-24 and SAH03 behave like slow two-step inactivators or reversible inhibitors, with a very low reverse isomerization rate.

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Metadaten
Author:Aleksandra Kopranovic, Franz-Josef Meyer-AlmesORCiD
URN:urn:nbn:de:hebis:ds114-opus4-4414
DOI:https://doi.org/10.3390/ijms25115593
ISSN:1422-0067
Parent Title (English):International Journal of Molecular Sciences
Publisher:MDPI
Place of publication:Basel
Editor:George Mihai Nitulescu
Document Type:Article
Language:English
Year of Completion:2024
Publishing Institution:Hochschule Darmstadt
Release Date:2024/06/17
Tag:binding mechanism; drug–target interaction; histone deacetylases; protein–ligand binding
GND Keyword:-
Volume:25
Issue:11
Article Number:5593
Note:
Originalveröffentlichung: Kopranovic, A.; Meyer-Almes, F.-J. Rapid Determination of Kinetic Constants for Slow-Binding Inhibitors and Inactivators of Human Histone Deacetylase 8. Int. J. Mol. Sci. 2024, 25, 5593. https://doi.org/10.3390/ijms25115593
Institutes:Chemie- und Biotechnologie
OpenAIRE:OpenAIRE
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International